Mechanisms of Aging and Neurodegeneration

Mechanisms of Aging and Neurodegeneration

Exploring Thiamine Deficiency, Catecholamine Toxicity, and Angiotensin II

Quinn Rivet, ND

Exploring how thiamine deficiency, catecholamine-induced neurotoxicity, and Angiotensin II contribute to neurodegeneration and aging in the brain.

Introduction

This paper aims to explore specific pathological mechanisms involved in neurodegeneration and the aging brain. By clarifying these mechanisms, clinicians can better identify therapeutic targets and implement more effective treatment strategies. Scientists have been working diligently alongside clinicians over the years, and this paper presents some of their key findings. Several human clinical trials based on these findings provide further credibility to the clinical applications noted in this paper. 

The following sections will explore how altered thiamine influences critical enzymes within the glycolytic pathway, Krebs cycle, and Pentose Phosphate Pathway (PPP), resulting in inefficient energy metabolism and impaired synthesis of essential molecules (e.g., myelin via PPP) in the brain. These disruptions are believed to contribute to certain clinical neurological deficits. 

The paper also examines catecholamine-induced neurotoxicity, which results from the spontaneous oxidation and/or metabolism of catecholamines through the monoamine oxidase system, producing neurotoxic aldehydes. This process is regarded as a key pathogenic mechanism in stress-related neurological damage linked to conditions such as Alzheimer’s and Parkinson’s, as well as in general brain aging. 

Finally, the role of Angiotensin II—typically associated with the cardiovascular and renal systems–is examined in the context of neurodegeneration. Emerging evidence indicates that Angiotensin II is synthesized locally in the brain, where it contributes to neurodegeneration by upregulating microglia and promoting neuroinflammation, linking it to both disease-related and age-related cognitive decline.

While other mechanisms, such as the gut-brain axis, neurotrauma, and infection, have been explored in separate research articles, this paper focuses on understanding the aforementioned mechanisms. It aims to enhance clinicians’ understanding of the pathophysiological processes contributing to both age-related and disease-related neurological deficits.

Thiamine Associated Neurodegeneration

Dr. Rudolph Peters, an English medical doctor and biochemist, could arguably be considered the father of functional medicine. He became the chair of chemistry at Oxford at age 34 and was associated with over 200 published papers throughout his career.1 His first paper, published in 1912, elucidated oxygen and its relationship to hemoglobin.2 

He later researched the toxicity of certain gases using protozoa1, which led him to investigate the nutritional requirements of the media used to sustain these organisms. This exploration eventually motivated him to study B-complex vital amines (i.e., vitamins). He worked with the factor that helped cure pigeons and other fowl suffering from beriberi. He observed that pigeons with this factor deficiency exhibited certain symptoms, such as ataxia and opisthotonos.

By 1932, he and his colleagues had isolated a factor from yeast that demonstrated high vitamin B1 activity. He observed that when this factor (thiamine) was administered to birds with a deficiency induced by a polished rice diet, there was an improvement in symptoms, particularly head retraction. He believed this deficiency indicated “underlying damage to the nervous system.” While thiamine deficiency caused peripheral polyneuropathy, he thought it also had a significant central impact, specifically in the brain. 

Fundamentally, Peters was the first to demonstrate the mode of action of a vitamin; in this case, he concluded that it influenced a pyruvate enzyme.3 Notably, he also coined the term “biochemical lesions” to refer to a low functional enzyme state caused by “cofactor” insufficiency or a toxicant that negatively impacts the function of certain biochemical pathways (hence, he is regarded as the father of functional medicine).4 

Science has also noted over time that thiamine deficiency (beriberi/Wernicke-Korsakoff syndrome) has similar neurological symptoms to those of other neurological conditions such as dementias and Alzheimer’s.5-9 Over time, papers were published exploring thiamine and its role in brain metabolism, including the cholinergic system.10-22 It has been determined that thiamine insufficiency profoundly influences three main enzymes involved in energy metabolism23: 

  • Transketolase influences the pentose phosphate shunt, which is important for myelin and NADPH production involved in glutathione activity.
  • Pyruvate dehydrogenase fundamentally links glycolysis to the Krebs cycle and alpha-ketoglutarate complex, serving as the rate-limiting step in the citric acid cycle. 
  • Alpha-ketoglutarate complex is a rate-limiting step in the Krebs cycle.

The downregulated activity of these enzymes may be due to several factors: low intake of thiamine (e.g., alcoholism), interrupted absorption, poor transport into the cell, or issues with enzyme activation. With these enzymes downregulated, primarily essential cellular functions, including beta-amyloid production and increased oxidative stress, have been noted.24,25 The end result is poor functioning of neurons and upregulation of microglial activation, which is related to neuroinflammation, damage, and expression of clinical entities. 

It is now understood how apparent insulin resistance can occur in neurodegenerative diseases, particularly Alzheimer’s26,27, when glucose metabolism is significantly altered downstream. Additionally, a high oxidative environment can influence receptor and secondary messenger systems, exacerbating mitochondrial dysfunction due to sustained and unabated oxidative stress within the neuro-microenvironment.28,29

Figure 1 depicts the three main enzymes that use thiamine as a cofactor. Insufficient cofactors can lead to reduced enzyme activity, which may result in a cellular degenerative state and decreased functionality. This can instigate clinical symptoms such as poorer cognition and psychic, motor, and somatosensory disturbances. 

The clinical application of thiamine pyrophosphate (ThPP) during periods of overt deficiency has been noted to be curative (R). However, in chronic cases of mild cognitive deficit or early Alzheimer’s, water-soluble thiamine does not appear to cross the blood-brain barrier or remain interneuronally in sufficient quantities (R). Therefore, synthetic thiamine has been developed with greater fat solubility, allowing for better absorption and a more enhanced effect on the enzymes: transketolase, pyruvate dehydrogenase, and the alpha-ketoglutarate complex intraneuronally. Small human clinical trials have yielded promising results.30-41

“Among these, the thioester benfotiamine (BFT) has been extensively studied and has beneficial effects both in rodent models of neurodegeneration and in human clinical studies. BFT has antioxidant and anti-inflammatory properties that seem to be mediated by a mechanism independent of the coenzyme function of ThDP. BFT has no adverse effects and improves cognitive outcome in patients with mild Alzheimer’s disease (AD). Recent in vitro studies show that another thiamine thioester, dibenzoylthiamine (DBT), is even more efficient than BFT, especially with respect to its anti-inflammatory potency.”30

Angiotensin II-Related Neurodegeneration

Angiotensin II (Ang II) is usually considered in the context of renal and cardiac disease; however, in recent decades, it has been found localized in the brains of rats41, which has led to human studies revealing its role as a pro-inflammatory molecule.42,43 It is suggested that part of its inflammatory effects result from an upregulation of NADPH oxidase, causing increased oxidation related to brain injury and neurodegenerative diseases.44,45 

Interestingly, Angiotensin-II associated brain inflammation has been linked to hypertension46, heart disease47, heart failure and remodeling48,49, activated microglia in heart failure50,51 rats, aging in heart failure, and depression in heart failure52-54. Moreover, Angiotensin-II mediated neuroinflammation contributes to cognitive impairment55,56, including a potential association with Alzheimer’s disease.57 One proposed mechanism behind Ang II-mediated neuroinflammation is that the angiotensin II type 2 receptor (with Ang II as its ligand) can modulate a pro-inflammatory response in microglia and other cells, such as macrophages.58-63 Neurological damage arises from an increase in NADPH oxidase, which generates free radicals and pro-inflammatory transcription factors, leading to the elaboration of pro-inflammatory cytokines and ensuing neuronal damage, including damage to the blood-brain barrier.

Another mechanism at play is that Ang II has a detrimental effect on the blood-brain barrier64-70, increasing its permeability. This increased permeability allows Ang II to drift into brain areas, such as the hypothalamus and brainstem, which subsequently causes brain disruption.67 Ang II can also modulate sympathetic outflow by stimulating sympathoexcitatory centers.69 The latter results in increased catecholamine release, which enhances the aminochrome redox cycling pattern that, in itself, is neurodegenerative. 

However, the brain appears to have a counteracting system to balance this Ang II neuroinflammation, which is Ang 1-7.71-75 Literature reveals that when Ang 1-7 (with ACE 2 required for conversion from Ang II) binds to the Mas receptor, a cooling effect occurs, signaling a more anti-inflammatory and antioxidant state. With this anti-inflammatory state, neurodegeneration and, consequently, cognition may be mitigated. 

Fig 2. Ang II triggers microglial activation, leading to cytokine release that contributes to neurodegeneration and increases blood-brain barrier permeability.

Fig 3. Basic outline of the angiotensinogen pathway, showing receptor-dependent outcomes based on either Ang II or Ang 1-7, as well as therapeutic targeting, such as ACE inhibition. Studies have shown that ACE and ACER blockers may have neuroprotective qualities. 

With this association in mind–that is, the link between Ang II-mediated inflammation and its role in neuroinflammation and brain degeneration–several therapeutic strategies have been explored. These include:

  • Decrease Ang II  synthesis (via Renin or ACE inhibitor)
  • locking its receptor (using ACE receptor blockers)
  • Increasing Ang 1-7 levels or enhancing Mas receptor ligand
  • Mitigating the intracellular effects of toxic radicals

Natural ACE inhibitors have been investigated; many are polyphenolic in origin.84-86 However, these natural compounds often have relatively high IC50 values, so their effectiveness may be less pronounced in lowering critically elevated Ang II (e.g., renal-associated hypertension). Nonetheless, they may prove successful as a long-term addition to treatment. Their antioxidant qualities are undoubtedly advantageous.

Catecholamine-Related Neurodegeneration

Chronic stress in midlife has been observed to correlate with later life neurodegeneration, particularly Parkinson’s disease, Alzheimer’s, and age-related dementia87-89, as well as stress-induced cardiomyopathy.90 Literature shows that chronic stress, and consequently high neuro-catecholamine exposure, has a multifaceted cytotoxic effect on central neural tissue.91-100 

The metabolism of catecholamines (e.g., dopamine, norepinephrine) through the monoamine oxidase (MAO) enzyme system, along with spontaneous oxidation, results in the accumulation of toxic molecules such as aminochrome and its o-semiquinone radical. These molecules undergo REDOX cycling (see Fig. 4), producing hydrogen peroxide97, which can trigger a Fenton reaction when exposed to iron, generating hydroxyl radicals. This cascade leads to progressive damage to cellular mechanisms and architecture, particularly impacting mitochondrial function.95-98 

This pathway has been linked to the neurodegeneration processes involved in Parkinson’s disease, Alzheimer’s, and aging.101-106

Fig, 4 

A simplified version of catecholamine metabolism via MAO and spontaneous oxidation produces aminochrome, and through a one-electron reduction, forms the o-semiquinone radical. This radical subsequently generates hydrogen peroxide, which can create damaging hydroxyl radicals. The hydrogen peroxide is converted to water and oxygen by glutathione, which is then re-reduced to its active form by glutathione reductase, which requires NADPH from the pentose phosphate pathway. If aminochrome redox cycling outpaces the in situ activity of glutathione—either due to a lack of substrates, insufficient selenium for glutathione peroxidase, or an issue with NADPH—a high concentration of oxidative molecules will form, leading to eventual neurodegeneration. This heightened redox cycling can also deplete NADH as it is diverted to the redox cycling, reducing its availability for mitochondrial electron transport and subsequently lowering ATP synthesis. This reduced ATP synthesis, combined with the increased redox cycling of aminochrome and its semiquinone producing neurotoxic hydrogen peroxide, disrupts neuronal allosteric balance, contributing to neurodegeneration and all the associated cascades, ultimately leading to cognitive and psychiatric pathologies.

Chronic stress has been shown to trigger inflammatory activity not only in peripheral immune cells and cytokines but also by enhancing the activation of glial cells within an inflammatory context.107 This leads to increased production of inflammatory cytokines in the brain, which contributes to subsequent clinical manifestations such as anxiety, depression, psychosis, and central degeneration, including cognitive deficits. 

Activated MAO also contributes to amyloid (Aβ) aggregation by producing two successive cleavages of amyloid precursor protein (APP) via beta-secretase and gamma-secretase.107,108 This process and the destruction of cholinergic neurons lead to cognitive impairment. 

Given this association, it seems prudent to inhibit MAO as a potential treatment for neurodegeneration–an approach that has been utilized for some time. Depression in dementia has been treated with MAO inhibitors since at least 1985.109 Furthermore, MAO inhibitors have remained a key focus of treatment over the years for Alzheimer’s110-117 , and perhaps this model could be adapted for prevention strategies to mitigate neurodegeneration.

A combination of MAO oxidase inhibitors and acetylcholinesterase inhibitors has also been explored for Alzheimer’s disease.118 This combined approach may offer anti-Alzheimer’s and neuroprotective effects by reducing oxidative stress caused by MAO enzyme activity.

Certain plants may have therapeutic effects with this model in mind. Ege et al. report69 that quercetin, epigallocatechin gallate, resveratrol, curcumin, as well as Angelica gigas and Scutellaria baicalensis exhibit MAO inhibition effects and possess antioxidant properties. Hypericum perforatum has been noted as an MAO inhibitor.70 Dat, T., et al. report that 51 plants were evaluated for their MAO inhibitor properties, though human trials are still lacking.71 Finally, Polygonatum sibiricum has been investigated for its neuroprotective properties.72  

It appears clinically prudent to support glutathione (e.g., NAC, selenium), enhance intraneuronal antioxidant capacity including mitochondrial protection (e.g., ALA, CoQ10, carnitine), and replenish cofactors involved in protecting against highly cytotoxic hydrogen peroxide. Lastly, and most obviously, it is essential to minimize catecholamine influx to avoid overburdening neural cells, which could perpetuate and/or accelerate existing neurodegeneration; in other words, one must manage sympathetic output. 

Quinn Rivet, ND graduated from CCNM in 1994. From 1997-2000 he instructed at CCNM and was a clinical supervisor. From 2001 to 2012 he was an instructor of pathology, laboratory diagnosis, nutrition, clinical medicine, and the chair of Nutrition (2004-2010) at Boucher Institute of Naturopathic Medicine. After returning from 3 years in China (2017-2020) where he taught English and explored TCM for IgA nephropathy, Dr Rivet now pursues further work in clinical research, education, and consultation services at The Miramichi Naturopathiuc Health Clinic (MiramichiNaturopathic.com). Inquiries:  drquinn@shaw.ca.

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