u/gogge

I've seen at least one RCT supporting your point that it's not about red meat protein itself; In the (Toh, 2024) RCT they looked at 8 weeks of a vegan to normal diet when explicitly using meat replacements to minimize the diet differences and found no meaningful change:

There were no significant effects on the lipoprotein profile, including LDL-cholesterol.

Diastolic blood pressure (DBP) was lower in the PBMD group (PInteraction=0.041) although the nocturnal DBP markedly increased in ABMD (+3.2% mean) and was reduced in PBMD (-2.6%; PInteraction=0.017). Fructosamine (PTime=0.035) and homeostatic model assessment for β-cell function were improved at week 8 (PTime=0.006) in both groups.

Glycemic homeostasis was better regulated in the ABMD than PBMD groups as evidenced by interstitial glucose time in range (ABMD median: 94.1% (Q1:87.2%, Q3:96.7%); PBMD: 86.5% (81.7%, 89.4%); P=0.041).

...

Among the other cardiovascular health-related outcomes however, no time and interaction effects were observed in terms of the clinic SBP, hsCRP concentrations, and Framingham 10-y CVD risk following the 8-week intervention.

There are some new preliminary results, just this November, from the Lp(a)HORIZON RCT indicating that Lp(a) likely isn't a modifiable risk factor in established CVD (Novartis):

"Although lower Lp(a) levels were observed with pelacarsen, the findings did not demonstrate that this translated into reduced cardiovascular risk in the overall study population. These are not the results we hoped for, but they provide important evidence that advances scientific understanding of the relationship between Lp(a) lowering and cardiovascular outcomes and may help inform future approaches to cardiovascular risk management. We thank the more than 8,000 trial participants and investigators who made this study possible, and remain committed to driving cardiovascular innovation."

There's also a JAMA article from last week with some researcher opinions on the study: "Lp(a)-Reducing Agent Pelacarsen Misses the Mark in Phase 3—Now What?".

You said:

This study is based on the non-ultra processed meal (hard boiled eggs, banana, cranberries, cheese, sea salt) being nutritionally identical to the UPF meal in terms of what you’d see on a nutrition facts label. But the UPF meal is deli turkey, instant mashed potatoes, a CHOCOLATE CHIP COOKIE, FROSTED WHEAT cereal, veggie chips, white bread, peanut butter, jelly, and water. There’s no way that’s true.

The macronutrient breakdown shows that the meals were balanced, so that there were 10g of chocolate chip cookies in the UPF group is irrelevant.

Comparing the list to foods in the USDA database shows that the non-UPF meal is ~6.4 g SFA and the UPF meal is ~3.7 g. For sugar it's ~36 g non-UPF vs. ~10 g UPF, with a possible question around sweetened vs. unsweetened cranberries.

non-UPF:

UPF:

Every aspect of foods doesn't have to be included in the study, for example they didn't balance texture/color/smell either, but that doesn't invalidate the findings. People would just do another trial that looks at that if it seems like a relevant factor. Same thing for micronutrients.

They match on the macronutrient level, so that they ate 10 grams of chocolate chip cookies isn't relevant?

They have the breakdown of the example meal in the source RCT paper (Hutelin, 2026):

Fig. 1b

The non-ultraprocessed and ultraprocessed meals used in the metabolic sessions were derived from a 300 kcal subset of the 28 foods used in the picture set^21. The nutritional information for all 28 foods was derived from the Nutrition Data System for Research (version 2022) and then entered into an algorithmic process of testing combinations of different food pairings with different portion sizes to identify the most nutritionally matched set of non-UPF and UPF meals. Through this process, the final non-UPF and UPF meals were matched on weight, energy, energy density, total carbohydrates, total fats, total proteins, available carbohydrates, glycaemic index, glycaemic load, total dietary fibre, sodium and water, all with <1.6% error between meals. To match weight, energy, energy density and water, a 12 g serving of water was added to the UPF meal. Nutritional information and a list of the foods are available in Fig. 1b.

The meals look fairly balanced.

I have no idea how you got that from what the studies show, can you elaborate?

How does it not do that? The meta-analysis show that ketogenic diets lead to better improvements even when isocaloric:

Isocaloric vs. non-isocaloric comparisons showed similar patterns, suggesting macronutrient composition alone may engender beneficial metabolic effects.

They compared to high carb diets as the control group so you know the higher insulin sensitivity is from the diet and not weight loss.

Probably not.

From a quick look meta-analyses of observational data on MASLD/NAFLD indicate a lower risk (Yuzbashian, 2023):

Out of 1206 articles retrieved, 11 observational studies, including 43,649 participants and 11,020 cases, were included. Pooled ORs revealed that milk (OR: 0.86; 95% CI: 0.78, 0.95; I2 = 65.7%, n = 6), yogurt (OR: 0.88; 95% CI: 0.82; I2 = 0.0%, n = 4), and high-fat dairy (OR: 0.38; 95% CI: 0.19, 0.75; I2 = 0.0%, n = 5) consumption was inversely associated with NAFLD while cheese was not linked to NAFLD risk.

And there's no association with T2DM in meta-analyses of observational studies (Gijsbers, 2016):

Total milk intake (11 studies) (10, 11, 13, 14, 15, 16, 22, 23, 24, 26, 28) was not associated with T2D risk (RR: 0.97 per 200 g/d; 95% CI: 0.93, 1.02; P = 0.25) (Supplemental Figure 17).

Similar findings in a more recent narrative review on T2DM and dairy looking at the overall evidence (Vimaleswaran, 2026):

The objective of this review is to highlight the effect of dairy intake on T2D and MetS using recent evidence (published within the last decade) from large epidemiological studies, meta-analyses, randomized controlled trials (RCTs), and Mendelian randomization (MR) and multi-omics studies, and to provide plausible underlying biological mechanisms linking dairy consumption with the risk of T2D and MetS.

...

For milk, most studies were either protective or neutral, with very few showing a deleterious effect, and with respect to cheese and butter, there were studies showing a deleterious effect, but the grade of evidence was weak.

There's a study by (Volk, 2014) where they look at HOMA-IR of people gradually increasing carbs after improvement and see no issues:

Fig. 2C.

Each phase is 3 weeks.

There also was a recent RCT, unfortunately no meta-analyses from what I've seen, showing a ketogenic being better at "mobilizing fat in the liver" (Petersen, 2026):

Weight loss increased muscle insulin sensitivity by ∼50% in all groups but caused a two-to-three-fold greater increase in hepatic insulin sensitivity in the very-low-carbohydrate group than the other groups (p < 0.001). Intrahepatic triglyceride content, hepatic de novo lipogenesis, glycated hemoglobin, and 24-h serial plasma glucose and insulin decreased most in the very-low-carbohydrate group.

A good recent review on ketogenic diets and reduction of liver fat is (Emanuele, 2025):

In this context, the very-low-calorie ketogenic diet (VLCKD) has emerged as a promising intervention for MASLD due to its ability to induce rapid weight loss and substantial reductions in hepatic steatosis and visceral adiposity [16,18,19].

Meta-analyses show that low carb diets improve insulin resistance more than higher-carb diets, especially ketogenic diets (Feng, 2025):

149 randomized controlled trials comprising 9104 adults across 28 countries were included. CRDs significantly improved glycemic control (including glucose: SMD = -2.94 mg/dL, 95 % CI: -4.19, -1.68; insulin: SMD = -8.19 pmol/L, 95 % CI: -11.04, -5.43; HOMA-IR = -0.54, 95 % CI: -0.75, -0.33), hepatic stress (GGT: SMD = -6.08 U/L, 95 % CI: -9.97, -2.20), renal function (UACR: SMD = -0.19, 95 % CI: -0.28, -0.10), and adipokine concentration (leptin: SMD = -3.25 ng/mL, 95 % CI: -4.91, -1.59), particularly in females, individuals with overweight/obesity, and people with T2DM.

...

Among participants with KD, compared to higher-carb diets, improved metabolic health was shown in reductions of glucose (−4.59 mg/dL), insulin (−9.81 pmol/L), and HOMA-IR (−0.63).

Meta-analyses of ketogenic diets for weight loss show a similar decrease in LDL-C, a greater decrease in triglycerides, and that they better maintain HDL-C levels, compared to higher-carb diets, which reduces the risk of CVD (Muscogiuri, 2021):

A significant reduction in LDL of −9.04 mg/dL from baseline to follow-up after a VLCKD [Very Low-Calorie Ketogenic Diet] (95% CI −13.94 to −4.15; I2 = 29%) was observed. However, a VLCKD did not demonstrate a superior effect in terms of LDL reduction compared to other weight loss diets (p = 0.12; Fig. 3y, z). HDL showed no change from baseline to follow-up after a VLCKD (p = 0.85), and interestingly when we compare the mean change in HDL cholesterol between a VLCKD and other weight loss interventions we noticed a significant difference between the two (+3.14; 95% CI 0.70–5.59; I2 = 84%; p = 0.01; Fig. 3aa, 3bb). Finally, a significant reduction in TG (−49.68 mg/dL: 95% CI −58.81 to −40.55; I2 = 55%) was observed after a VLCKD. The reduction of TG was larger after a VLCKD (∼–29.90 mg/dL; 95% CI −42.47 to −17.32; I2 = 89%; p < 0.00001) compared to other diets (Fig. 3cc, dd).

It's usually long term studies that show no, or negative, results that also tend to have adherence problems, eg. +6.35 mg/dL LDL-C after 12 months in type 2 diabetics but likely no longer ketogenic (Patikorn, 2023):

Lastly, due to decreased adherence, carbohydrate intake most likely increased across the course of the trials. For example, subjects in the KD arm of the A TO Z Weight Loss Study, started with a carbohydrate intake < 10 g/day but ended at 12 months with a carbohydrate intake accounting for 34% of TEI.

In general the best diet is the one people can stick to; if it's Keto, WFPB, DASH, Mediterranean, etc. doesn't really matter.

They used 0.45 g/kg in the first study and then more than doubled it to 1.3 g/kg for the second study, which is more than adequate and likely removes any limitations on MPS from the lower amino acid content of plant protein.

Reference 32 is (Pinckaers, 2023):

On one day, participants consumed a whole-food omnivorous meal containing beef as the primary source of protein (0.45 g protein/kg body mass; MEAT). On the other day, participants consumed an isonitrogenous and isocaloric whole-food vegan meal (PLANT).

Reference 33 is (Domić, 2025):

The small difference in analyzed protein contents between the diets (vegan, 19.9 en%, 1.3 g/kg compared with omnivore, 18.1 en%, 1.2 g/kg) could be considered negligible.

A research dietitian coached them repeatedly, three sessions in total, on vegan recipes and the importance of protein:

During the monthly nutrition information meetings (Figure 1), the VEG and VEG-RE groups were informed regarding suitable plant-based replacements for animal-based food products by a research dietitian. During the meetings, guidance was provided regarding the adoption of a vegan diet, and participants were given the opportunity to address any questions or concerns related to their diet. Although all nutrients were considered in the information provided during these meetings, additional emphasis was placed on nutrients that are of particular concern later in life, namely, protein, cobalamin, calcium, iron, and the importance of vitamin D supplementation. The content presented during these meetings was based on the Dutch national dietary guidelines, excluding their recommendations regarding animal-based food products. The participants were equipped with practical tools, including vegan recipes and pocket-size handouts containing, for example, vegan product logos.

And from the study design (Domić, 2025):

During the nutrition information meetings, these groups will be informed regarding suitable plant-based replacements for animal- based food products, such as legumes, nuts, and dairy alternatives.

See (Geidl-Flueck, 2023) for a good review of the possible mechanisms of fructose and hepatic fat accumulation.

Looking at just DNL sugar/fructose roughly doubles hepatic DNL compared to just glucose, in healthy men, with no change in caloric intake (Geidl-Flueck, 2021):

This study demonstrates that daily consumption of beverages containing moderate amounts (comparable to those provided by commercial soft drinks/fruit juices) of either fructose or sucrose, but not glucose, increases hepatic FA synthesis in healthy men in a basal state. SSB consumption (with ad libitum meals) influenced absolute macronutrient intake (i.e. decreased fat and protein intake) but did not increase total energy intake.

But it's not just about fructose DNL, acutely fructose also increases liver/hepatic fat content (HFC) when co-ingested with dietary fat, in healthy people, and with NAFLD it's even more problematic (Kovar, 2021):

HFC increased by 10.4 ± 6.9% six hours after a high-fat load and by 15.2 ± 12.5% after high-fat load with fructose. When co-administering glucose with fat, HFC rose only transiently to return to baseline at 6 hours. Importantly, NAFLD subjects accumulated almost five times more fat in their livers than healthy subjects with normal HFC.

Slower absorption of the fructose likely helps, like with some types of fruit. Exercise and/or a caloric deficit might also help mitigate the overall metabolic dysfunction, even if it might not affect hepatic DNL directly. From the Geidl-Flueck, 2023 review above:

Overall, findings from various clinical studies indicate that carbohydrates, particularly when consumed as simple sugars and in liquid form, promote hepatic lipogenesis even when maintenance dietary interventions are used.

...

Eight healthy men were placed on a weight-maintenance high-fructose diet (SSB) for 4 days before the metabolic fate of 13C-labeled fructose with or without physical activity was investigated. Exercise increased fructose oxidation. However, it did not abolish fructose conversion into glucose or did not prevent DNL (AUC of VLDL-13C palmitate). These findings imply that fructose-induced DNL occurs regardless of the degree of saturation of other fructose metabolism pathways.

A lack of studies means it's far from settled, or fully explained.

In the methods section under "Diet intervention" they have examples of the diets:

The entrees of the very-low-carbohydrate ketogenic diet included but were not limited to: egg salad, omelet with bacon and sausage, almond flour French toast muffin, cheesy beef, pulled pork, Italian chicken with spinach, pecan-encrusted tilapia, salmon with cauliflower mash, pot roast, salmon with broccoli, and chicken with asparagus.

The entrees of the Mediterranean diet included but were not limited to: oatmeal with almonds and blueberries, vegetable breakfast hash, mixed berry smoothie, minestrone, spicy tilapia, salmon succotash, quinoa with black beans and corn, chicken pesto pasta, arancini, vegetable burger with roasted sweet potato, and vegetable flatbread.

The entrees of the very-low-fat plant-forward diet included but were not limited to: apple banana oatmeal, breakfast potato bake, fruit smoothie, red beans and rice, vegetable tortilla wrap, mixed grains with salmon, vegetable shepherd’s pie, sweet potato and black bean soup, and vegetable chili.

...

Participants met weekly with the study dietitian to review food logs, barriers to full adherence, adverse events, and any medication changes or intercurrent medical events.

...

Dietary adherence, assessed as the percentage of study meals and snacks that were logged as consumed, was greater than 95% in all diet groups (Table S2).

There are no issues with the methods of the study that I've noticed.

Much of the effect is weight loss, but the carbohydrate restriction in ketogenic diets shift the metabolism to spare glucose, and instead increase fat oxidation and ketone use, which tends to bring down insulin levels.

So generally if the underlying metabolic issue is related to insulin resistance and/or glucose metabolism, e.g T2DM, so it might be beneficial.

Have a look at (Chen, 2023), it's an umbrella review of meta-analyses, and Table 1 lists what subjects/factors they include. It might have some meta-analysis that looks at issues related to your situation, or the meta-analysis might have individual studies that are relevant.

It's an "ok" trial, Fig 1 has a good overview; it's an RCT, they provided the food, ~5 months of weight loss with 3-4 weeks weight maintenance, but it's only 14 subjects per group:

However, our study’s sample size was small, so it is possible that some differences among diet groups were missed because of inadequate statistical power.

Looking at other studies these findings aren't novel, reviews also show the same benefits of ketogenic diets on liver markers (Emanuele, 2025):

The analysis indicates that ketogenic diets significantly reduce hepatic fat content and improve metabolic parameters, including insulin sensitivity and liver enzyme levels.

And more generally for "metabolic health" a meta-analysis shows the same (Choi, 2020):

Our study findings confirmed that ketogenic diets were more effective in improving metabolic parameters associated with glycemic, weight, and lipid controls in patients with overweight or obesity, especially those with preexisting diabetes, as compared to low-fat diets.

So this study is ok, and it shows similar findings to other studies.

It was retracted by the authors themselves, not the journal, because the third party that did the plaque scans failed to follow protocol on the noncalcified plaque volume (NCPV) analysis.

Two other independent analyses showed less progression in NCPV than the initial analysis.

Article by Norowitz.

Figure 4 shows that the lean mass gain was mostly in the initial 6 weeks with no meaningful change week 6 to 12, so it's likely just water.

Looking through the studies this feels very speculative.

In general meta-analyses of RCTs indicate that there's no benefit to eating less protein, specific amino acid restriction might have effects in some cases, but broadly speaking we usually see slight benefits with higher protein intakes.

The first (Knopf, 2026) reference is (Sluijs, 2010) looking at data from the observational EPIC-NL study, and they saw a doubling or T2DM risk (RR 2.15), with adjustments making no difference.

A 100% increase in risk should be very visible in RCTs on T2DM.

But looking at meta-analyses of RCTs in T2DM we see mostly non-significant trends towards benefits with higher protein intake, aside from a slight improvement in HOMA-IR in a few studies (Yu, 2019):

Glycemic control was not significantly different between the high-protein diet and control group, with the changes in fasting plasma glucose (FPG) (-0.13 (95% CI (-0.46, 0.19), p = 0.43) mmol/L) and HbA1c% (-0.05 (95% CI (-0.18, 0.08, p = 0.92))) from baseline to the end of intervention. However, the difference in IR between the two groups was statistically significant.

...

The change in HOMA-IR between the baseline and the end of the intervention was -0.27 (95% CI (-0.47, -0.06), p < 0.01).

...

Our analysis revealed a mild reduction in HOMA-IR, but only three eligible trials were included.

And similarly we see beneficial effects on weight and HOMA-IR in people with pre-diabetes (Hansen, 2021):

Individuals with prediabetes were found to benefit more from a diet high in protein compared to individuals with normoglycemia, as did individuals without the obesity risk allele (AA genotype) compared to individuals with the obesity risk alleles (AG and GG genotypes).

So is seems likely that the observational studies are picking up the effects of some residual confounding variables, or similar issues.

As for the protein restriction RCT (Fontana, 2016) showing improvements it's not surprising as they're losing weight, you see the same improvements in high protein diets. Comparing high to low protein diets in meta-analyses there's no meaningful difference, but a slight edge to higher protein (Santesso, 2012).

Skimming through the Santesso meta-analysis there's a study that has a 66.7 g/d protein intake vs. 121.4 g/d in obese/overweight subject, similar to the Fontana study, and the protein group had slightly better results (Lasker, 2008):

There was a trend for PRO to lose more weight (-9.1% vs. -7.3%, P = 0.07) with a significant reduction in percent fat mass compared to CHO (-8.7% vs. -5.7%; P = 0.03). PRO also favored reductions in triacylglycerol (-34% vs. -14%; P < 0.05) and increases in HDL-C (+5% vs. -3%; P = 0.05); however, CHO favored reduction in LDL-C (-7% vs. +2.5%; P < 0.05). INS responses to the meal challenge were improved in PRO compared to CHO (P < 0.05) at both 1 hr (-34.3% vs. -1.0%) and 2 hr (-9.2% vs. +46.2%), an effect that remained significant after controlling for weight or fat loss (both P < 0.05).

So the Fontana results are questionable.

For "strength athletes going for maximum hypertrophy" it's worth pointing out that the 1.6 g/kg/d mostly from studies in untrained subjects starting resistance exercise, and they didn't look specifically at the effect of caloric restriction, so it likely doesn't reflect the real upper bound for resistance trained individuals.

When looking at resistance trained individuals, especially combined with caloric deficits, the recommendations go up to potentially 3.1 g/kg/d (Jäger, 2017):

For building muscle mass and for maintaining muscle mass through a positive muscle protein balance, an overall daily protein intake in the range of 1.4-2.0 g protein/kg body weight/day (g/kg/d) is sufficient for most exercising individuals, a value that falls in line within the Acceptable Macronutrient Distribution Range published by the Institute of Medicine for protein. Higher protein intakes (2.3-3.1 g/kg/d) may be needed to maximize the retention of lean body mass in resistance-trained subjects during hypocaloric periods. There is novel evidence that suggests higher protein intakes (>3.0 g/kg/d) may have positive effects on body composition in resistance-trained individuals (i.e., promote loss of fat mass).

Details on the problems with the protein references in the Dietary Guidelines For Americans:

In the Dietary Guidelines the rapid systematic review of 30 RCTs, for the 1.6 g/kg/d recommendation, didn't look at the effect of resistance training, see appendix 4.9 in The Scientific Foundation For The Dietary Guidelines For Americans Appendices.

In the "proper" meta-analysis for the 1.6 g/kg/d basis, reference 240 in The Scientific Foundation For The Dietary Guidelines For Americans, only 10 out of 49 studies were in resistance trained (Morton, 2018):

A total of 49 studies from 17 countries met the inclusion criteria (figure 1). There were 10 studies in resistance-trained participants and 14 study groups in exclusively female participants.

Edit:
Clarified that it's untrained subjects starting RE.

Skimming the article I can can't see that they measured any water content.

They used 3-comparement DXA; bone, muscle, fat, with no mention of measuring total body water, intra/extracellular water, etc.

So it's likely just water, as we know creatine induced changes in total body water shows up as lean mass increases in DXA, 1.1 kg over 1 week (Buck, 2023):

FFM increased more in the creatine group than the placebo group measured by all body composition modes (1.2 kg, 1.9 kg, and 1.1 kg increase for SF-BIA, MF-BIA, and DEXA respectively, P<0.05).

...

Changes in body composition that occurred due to the increase in TBW were detected as an increase in FFM measured by SF-BIA, MF-BIA, and DEXA.

Edit:
Should be "can't see" that they measured water.

US red meat consumption has been stable, or slightly decreasing, since the 60s (FAO, via Our World in Data):

Per capita meat consumption in the United States

Meanwhile colorectal cancer rate ages 20-49 has increased by about 50% since just 1998 (Cancer.org):

Colorectal Cancer Incidence Rates by Age and Sex, 1998-2022, United States

So some other factor has likely changed, like the obesity epidemic (Chen, 2024):

These findings suggest excess body weight substantially contributed to and is likely a primary driver of the rising incidence of EOCRC [early-onset colorectal cancer] in the United States.

The PDF link has the full study in pre-print format:

https://link.springer.com/content/pdf/10.1186/s12937-026-01368-w_reference.pdf

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Before climate change we were likely at the natural "peak" of the current interglacial, temperatures have been roughly stable the last few thousand years (University of Arizona article):

Fig. 1

The last ice age was just 25k years ago, here's a chart over the last ~150k years (Kansas Geological Survey article):

Fig. B2

Edit:
Better phrasing.