Healthspan

Healthspan Research Review | Beyond Plaques: How Methylene Blue and Ketones Address Vascular-Hypometabolism in Alzheimer’s Disease Alzheimer’s disease (AD) is often associated with amyloid plaques and neurofibrillary tangles, yet growing evidence supports a vascular-hypometabolism hypothesis in which cerebral hypoperfusion and mitochondrial dysfunction—particularly at the level of cytochrome c oxidase—drive early disease processes. Research led by Dr. Francisco Gonzalez-Lima highlights pronounced deficits in oxidative energy production within critical brain regions such as the posterior cingulate cortex, correlating with cognitive decline and disease duration. These findings challenge the predominant amyloid-centric model by emphasizing the role of impaired blood flow and metabolic failure. Consequently, interventions targeting these core vulnerabilities—including methylene blue, ketone-based therapies, and near-infrared light—show promise in restoring mitochondrial function, enhancing oxygen utilization, and potentially slowing AD progression. By reframing AD as a hypometabolic disorder rooted in vascular and mit

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Ultimately, this review reframes Alzheimer’s as a hypometabolic disorder rooted in vascular and mitochondrial challenges, pointing to new opportunities for early detection, preventive care, and therapeutic approaches that surpass traditional amyloid-focused strategies.

He further examines evidence on potential synergistic interventions—including methylene blue, ketones, and near-infrared light—that aim to boost ATP production and improve cerebral blood flow, addressing the metabolic root of AD.

Drawing on autopsy data, imaging studies, and biochemical assays, Dr. LaFontaine shows how mitochondrial deficits in pivotal brain regions like the posterior cingulate cortex (PCC) correlate with cognitive decline and disease duration.

Instead of viewing amyloid accumulation as the initiating event, this hypothesis views impaired blood flow and mitochondrial dysfunction as key drivers of the neurodegenerative cascade.

Francisco Gonzalez-Lima at the University of Texas, which advances the vascular-hypometabolism hypothesis by focusing on declining mitochondrial function—particularly at the level of cytochrome c oxidase (CO).

and metabolic dysfunction often precede plaque buildup and may play an even more critical role in AD pathogenesis.

In this week’s Research Review, Dr. Rich LaFontaine, Healthspan’s Senior Scientist, highlights a groundbreaking line of research from the lab of Dr.

More than a century ago, Alois Alzheimer’s landmark findings on amyloid plaques and neurofibrillary tangles established the amyloid-centric model of Alzheimer’s disease (AD)—a perspective that has guided much of the field for decades. However, mounting evidence indicates that vascular insufficiency

Healthspan Research Review | Nature's Design Paradox: Aging as an Inherent Software Flaw Aging, that inevitable march towards senescence, has puzzled and intrigued scientists for centuries. Traditionally, our understanding of aging has centered on wear and tear, with the belief that our cells and tissues break down over time due to accumulated damage. However, a fresh perspective by Dr. João Pedro de Magalhães challenges this narrative, suggesting that the very processes responsible for our growth and development might also be driving our decline after we hit our reproductive prime.

Curious to dive deeper? Explore our analysis to learn how epigenetic clocks, cancer paradoxes, and species-wide comparisons all converge on one notion: aging might be a predictable, programmable process that we can slow—or even reset.

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From targeting pathways like mTOR/GH/IGF-1 to exploring partial cellular reprogramming, the prospect of true anti-aging therapies may rest on hacking the same software that built us in the first place.

💡 Key Takeaway

When we stop viewing aging as random decay and start viewing it as a continuation of developmental processes, new interventions emerge. Rather than playing “whack-a-mole” with diseases as they appear, we can aim to modify the genetic and epigenetic programs before pathology sets in.

• Full reprogramming poses cancer risks, but partial or cyclical approaches may offer a “factory reset” on aging without unchecked cell growth.

3️⃣ Cellular Reprogramming (Yamanaka Factors)

• Shinya Yamanaka’s breakthrough showed that four transcription factors (Oct3/4, Sox2, Klf4, c-Myc) can revert adult cells to a stem-cell-like state, effectively resetting epigenetic age.

• Metformin and calorie restriction both reduce IGF-1 levels, correlating with improved metabolic health and increased longevity in animal models.

• Rapamycin, by dialing down mTOR, extends lifespan in yeast, worms, flies, and mice—and is being explored in humans.

2️⃣ GH/IGF-1 Modulation (Metformin, Caloric Restriction)

• High GH/IGF-1 (Growth Hormone/Insulin-like Growth Factor) fosters rapid growth but can promote diseases in old age.

If our “developmental software” inadvertently fuels aging, slowing or resetting it could boost healthspan:

1️⃣ mTOR Inhibition (Rapamycin)

• mTOR drives cell growth and metabolism. Early in life, this is crucial for development. Later, overactive mTOR can accelerate tissue damage.

• Evolutionary Limitations: Natural selection strongly favors traits that help us pass on our genes, but it’s less “concerned” with what happens afterward—so flaws in the software persist.

🛠️ Interventions & Practical Applications

• Antagonistic Pleiotropy: Genes that are advantageous early in life (e.g., promoting growth, rapid cell division) can have detrimental effects later, once survival for reproduction is achieved.

Instead, we might be dealing with a quasi-programmed decline, where the very instructions that ensure reproductive success later drive degeneration.

• Similar dynamics appear in other tissues (hormone changes, immune shifts) past reproductive age.

📖 Why Does This Matter?

Traditional theories often treat aging as a linear accumulation of damage. But if aging is part of a developmental program, then wear and tear isn’t the sole culprit.

3️⃣ Maladaptive Developmental Software

• Phenomena like presbyopia—the stiffening of the eye’s lens—illustrate how growth-related processes beneficial in youth (lens expansion) can be harmful in mid-to-later life.

2️⃣ Predictable, Not Random

• Aging markers like grey hair or bone density loss unfold predictably, not chaotically.

• Across species—from mice to humans—the pace of development correlates with lifespan. Mice live fast and die young because their “growth software” runs at a breakneck speed.

• Dr. Steve Horvath’s work reveals that ~400 sites in our genome can predict chronological age with remarkable accuracy.

• This “clock” starts ticking almost from conception, suggesting aging isn’t random. Instead, it follows an orderly pattern written into our developmental script.

• Developmental Programs: These processes guide everything from cell division to tissue formation, but may later trigger deterioration.

📊 Core Findings & Perspectives

1️⃣ Epigenetic Clocks (Horvath Clock)

• DNA as Hardware: Our genetic code remains mostly stable—like the unchanging foundation of a computer.

• Epigenome as Software: Chemical marks (e.g., methyl groups) dynamically switch genes on/off, akin to software toggles.

But after hitting our reproductive prime, these same genetic scripts might start working against us, suggesting aging may be less about accumulated damage and more about developmental instructions gone awry.

Key Concepts from the Review:

🔍 The Research

In a his paper “Ageing as a software design flaw,” Dr. de Magalhães compares the epigenome to computer software that executes genetic instructions. Early in life, this developmental program orchestrates our growth from a single cell to a fully formed adult.

🧬 Is aging just wear-and-tear, or is it a built-in flaw in our biological “software”?

Dr. João Pedro de Magalhães proposes an interesting perspective: our DNA is the hardware, while the epigenome acts as software.

Over time, this “software” may become maladaptive, driving the aging

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New Research Review: The Surprising Role of Rapamcyin in Treating Long COVID and Post-Viral Symptoms: hspan.io/j5Cyvz

New Research Review: The Surprising Role of Rapamcyin in Treating Long COVID and Post-Viral Symptoms: hspan.io/j5Cyvz