Low Carb High Fat - Ketogenic

Remarks in no particular order:

While suggestive, one obvious caveat of this approach is that the minimally invasive and clinically ubiquitous physiological biomarkers most likely to be available in lifespan studies (e.g., HbA1c, BP, CRP) are not the most sensitive mechanistically.

BP can fluctuate easily and Hba1c is a weighted average of glycation, using an estimated 117 days for men and 106 days in women. Glucose levels on days nearer to the test contribute substantially more to the level of A1c than the levels in days further from the test. If the lifespan of the RBC are not near the average, then the reading will be skewed.

In contrast, blood CRP, indicative of inflammation, showed no significant changes around either landmark. n.s., not statistically significant

Curious that this marker inflammation would be have no statistical significance for brain network instability.

Further supporting the physiological biomarker and gene expression results, we demonstrated that an acute intervention that bypasses neuronal insulin resistance was able to reverse the aging effects. In this case, the fact that ketosis was induced within minutes was key in isolating mechanisms.

It is not clear if they also studied people who eat a diet that would result in more ketosis, or if they only induced ketosis in the participants of the study using exogenous ketones.

While our results implicate metabolic changes as occurring prior to vascular and immune changes, it is also important to consider that neuronal insulin resistance may itself be caused by even earlier age-related changes in neuronal mitochondrial functioning (74, 75)—an important topic for future research.

To be safe, probably best to start being metabolically healthy earlier rather than later.

Meanwhile, in agreement with our previous results in young adults, the glucose bolus calorically matched to each participant’s D-βHB dose did not show stabilizing effects in any of the age groups (Fig. 3C), indicating that the results were specific to non-GLUT4 (and thus noninsulin) mediated pathways.

Our body does not appear to need external sources of glucose to stabilize the networks in our brain.

One key conceptual challenge with devising a strategy for early intervention in brain aging is that the process involves many mutually interacting and reinforcing mechanisms.

Nice that they recognize that reductivism leads to poor conclusions.

For example, mitochondrial dysfunction can generate excessive reactive oxygen species that damage vascular endothelium and activate inflammatory pathways (61). This vascular damage is exacerbated by age-related reductions in cerebral blood flow, which compromise the delivery of nutrients and removal of metabolic waste products (62). The resulting tissue stress triggers microglial activation and promotes chronic low-grade inflammation or “inflammaging,” characterized by elevated proinflammatory cytokines that further impair metabolic and vascular function.

Very succinct summary of metabolic syndrome.

Blood–brain barrier dysfunction emerges as a critical nexus in this interaction, as it affects immune cell trafficking, metabolic substrate availability, and overall brain homeostasis (64). These changes are further complicated by cellular senescence, which affects all three systems through the senescence-associated secretory phenotype (SASP), promoting sustained inflammation and tissue dysfunction (65). This intricate interplay creates self-reinforcing cycles where dysfunction in one system can propagate through the others, potentially accelerating cognitive decline and increasing susceptibility to age-related neurological diseases.

Postulated mechanism for brain network instability as a result of MetS.

Dense paper that took me a while to get through, but worth the read.