#1

Abstract

The relationship between key energy metabolites and brain health is not well understood. We investigated the association between circulating ketone bodies, pyruvate, and citrate with cognitive decline, structural brain characteristics, and risk of dementia. We measured ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone), pyruvate, and citrate species using NMR in plasma samples from 1,850 older adults in the Cardiovascular Health Study collected in 1989-90 or 1992-93. Cognitive decline was assessed using the modified Mini-Mental State Examination and the Digit Symbol Substitution Test. Dementia was adjudicated by a committee of experts through comprehensive evaluations including cognitive tests, medical records, and interviews with the next of kin. Dementia-related mortality was confirmed by a committee using death certificates and other clinical data from hospitalization. Multivariable linear mixed models were used to assess 9-year cognitive decline, while multivariable Cox regression models evaluated 6-year dementia incidence and 22-year dementia-related mortality. White matter lesions and ventricular size were measured using MRI in 1992-94 and were analyzed using multivariable linear regression models. Higher plasma levels of ketones, particularly β-hydroxybutyrate, were associated with faster cognitive decline (β, -0.10; 95% CI, -0.15 to -0.05; Padj<.001) and dementia-related mortality (HR per SD, 1.29; 95% CI, 1.07 to 1.56; Padj=0.023). Higher pyruvate concentrations were associated with slower cognitive decline, smaller ventricular size, lower dementia risk (HR per SD, 0.87; 95% CI, 0.77 to 0.97; P=0.013; Padj=0.073), and lower dementia mortality. Higher citrate levels were associated with less cognitive decline and lower dementia risk. In adults aged 65 years and older, circulating ketone bodies are associated with faster cognitive decline and higher dementia mortality, while pyruvate and citrate are associated with lower dementia risk.

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#2

Pyruvate had the strongest association with dementia incidence, with a 13.3% lower risk (HR per SD, 0.87; 95% CI, 0.78 to 0.97; P=0.013; Padj=0.073) compared to a 6.9% for citrate (HR per SD, 0.93; 95% CI, 0.88 to 0.99; P=0.013; Padj=0.073; Supplementary Table 3).
In the aforementioned observational study in the UK Biobank, citrate was associated with increased incident dementia. Instead, our findings show a slower cognitive decline and a lower risk of incident dementia for this metabolite. Discrepancies may arise from variations in the adjudication of dementia.
In addition, prior evidence in vitro has demonstrated the downregulation of the enzyme citrate synthase in patients with AD, and thus of citrate, which aligns with our results. When excluding participants who did not meet fasting time criteria, citrate lost its significant association with incident dementia, but the difference in its effect size was not substantial.
We did not observe associations of citrate with white matter lesions, ventricular size, or dementia-related mortality.
Previous studies have shown that chronic insulin resistance, a key trait of type 2 diabetes, has been linked to both impaired brain glucose metabolism and increased dementia risk. However, in our study, the effect of the metabolites on dementia-related outcomes did not appear to vary based on dysglycemia status. We suggest that this might be attributed to an insufficient sample size. Additionally, age-related declines in growth hormones, such as IGF-1, which play a role in brain plasticity and cognitive function, could promote the metabolic shifts observed in our study.

#3

This is a contrarian idea, to what we have read elsewere.

#4

So it’s bull, they seem to admit

#5

Yes. That study is poorly designed because they applied a linear model while we know for sure that the ketones positive effects follows a U shaped curve. No ketones is not very good but too much ketones is ketoacidosis which is a life-threatening problem in a few hours.
Here is a plot showing how ketones will increase then fall with the progression of liver disease.

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#6

Several of the GHRH peptides increase IGF-1, one of the reasons I use them.

Because WADA is always looking for ways to detect use of PED’s, there are a number of excellent studies that demonstrate this.

#7

chris masterjohn recently had a post about sulfur and pyruvate…

Whether the GOT1/GOT2 transamination reaction occurs determines whether the H2S-producing reactions generate serine or pyruvate. Without the action of GOT1 or GOT2, the nitrogen is retained, generating serine alongside H2S via CSE or CBS. With the action of GOT1 or GOT2, as in the generation of H2S via CDO or MPST, pyruvate is produced.

Serine itself can be converted to pyruvate via serine dehydratase (not shown in the diagram).

Thus, producing H2S always has the ability to generate pyruvate, and necessarily produces pyruvate when it occurs via CDO or MPST.

Since pyruvate is a carbohydrate that is primarily derived from glucose during glycolysis, this means two things:

  • Carbohydrate restriction can hasten the generation of H2S by breaking down cysteine to get an alternative source of pyruvate.

  • Carbohydrate intake will tend to suppress H2S generation not only by removing the need to generate pyruvate but also by generating pyruvate and serine, which will collectively back up four H2S-producing reactions by product inhibition.