::: spoiler Summary

• Brain aging follows a nonlinear trajectory with distinct phases, including a critical window in midlife (ages 40-60) where metabolic interventions may be most effective.
• The onset of brain aging is marked by increased insulin resistance, which disrupts neuronal glucose metabolism and contributes to cognitive decline.
• Ketones, which bypass insulin resistance, can stabilize brain networks and potentially reverse early aging effects, particularly in the midlife critical window.
• The study identifies specific genes (GLUT4, MCT2, APOE) associated with brain aging patterns, highlighting the role of neuronal insulin resistance and ketone transport.
• Brain network destabilization accelerates after age 40, with the most rapid changes occurring between ages 60-70, indicating a critical period for intervention.
• The effects of ketones on brain network stability are most pronounced in individuals aged 40-59, suggesting a limited window for effective metabolic intervention.
• The study suggests that early metabolic stress in neurons, due to insulin resistance, can lead to irreversible damage if not addressed promptly.
• Gene expression analysis supports the role of insulin resistance in brain aging, with GLUT4 and MCT2 emerging as key factors.
• The study's findings align with broader aging biomarkers, linking molecular mechanisms to neurobiological outcomes.
• The research emphasizes the importance of early intervention in brain aging to prevent or delay cognitive decline and neurodegenerative diseases.
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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.

Just a moment...

(www.pnas.org)

The primary author also gives a talk about this paper, its great too

:::spoiler summerizer

New Research Pinpoints Midlife Brain Decline & How to Slow It

In this interview with Dr. Lily Mujica-Parodi and Dr. Kirk Nylen, they explore new research that identifies a critical age window for preventing midlife brain decline. They discuss the roles of metabolic health and ketones in stabilizing brain function, suggesting that insulin resistance may be a key driver of cognitive decline. The experts emphasize the importance of dietary changes, particularly reducing glycemic load, as a preventive measure against dementia and highlight the potential of ketogenic diets to enhance brain health. The dialog also addresses the interplay between diet, exercise, and metabolic processes in maintaining cognitive health into older age.

Key Points

Critical age window for intervention

The research suggests there is a crucial age window, particularly from the mid-40s to the 60s, where improvements in metabolic health can significantly affect brain function. Taking action during this time may prevent or slow cognitive decline.

Insulin resistance and brain health

Insulin resistance in neurons may contribute significantly to cognitive decline as individuals age, similar to insulin resistance in the rest of the body. Addressing this through dietary changes could be a strategy to maintain cognitive health.

Ketones as brain fuel

Ketones, derived from dietary changes like low-carb or ketogenic diets, serve as an alternative fuel source for brain activity when glucose metabolism is impaired due to insulin resistance, potentially reversing cognitive decline effects.

Lifestyle recommendations for prevention

The experts encourage proactive measures such as reducing glycemic load through dietary changes and increasing physical activity early in life, to establish healthy metabolic states that protect brain function.

Importance of biomarkers and monitoring

The discussion highlights the need for early detection of cognitive decline through advanced imaging and biomarkers, suggesting a new approach to preventive care similar to regular health screenings for other medical conditions.

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

Blood brain barrier may create a different environment for the brain, maybe its isolated from systemic inflammation?

Great notes! I liked your writeup

Thank you for linking her talk about the paper! It gives it so much more context. It's clear now that they studied a cohort who had already developed some brain network instability, and used exogenous ketones to induce ketosis in the participants, and Dr. Lily does mention a ketogenic diet as a means to get into ketosis as well.