Yes, PD is extremely heterogenous. That still doesn’t mean it’s a “phenotypic manifestation of brain aging”. But then again, if we posit that PD was absent or rare before the 1800’s then I am amazed to learn that there was no brain aging of that phenotype before 1800. Wonders never cease. And if brain aging was that radically different before 1800, then I see no logical reason - using the same criteria - why it wouldn’t change again in 2100 - hey, no more PD! Sorry, it’s nonsense word games. Look, we should concentrate on concrete pathologies manifest in various forms of PD. I see zero value in trying to color this under “brain aging phenotype”. YMMV.
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As you know I think Parkinsons and MND/ALS are actually accelerated aging of neurons compared to normal. Normally neurons and the CNS in general do not age as fast as other tissues. The heart and the liver also seem to have some protection.
However, when I wanted to put a poster to the Parkinsons research conference about this it was rejected on the abstract.
Why those neurons, because they have a large energy demand from OxPhos.
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The Gompertz-Makeham formula for mortality has the Makeham element which is external mortality. What has happened is a reduction in external mortality and child mortality.
We don’t really know what has happened in terms of PD prior to the 1800s.
However, I asked Gemini and I think you cannot post that PD did not exist before the 1800s.
While British physician James Parkinson published his definitive clinical description An Essay on the Shaking Palsy in 1817, the symptoms of what we now call Parkinson’s disease (PD) were recorded for thousands of years prior. Because early medicine classified disorders by individual symptoms rather than complex neurological syndromes, these historic accounts appear as fragments across ancient, medieval, and Enlightenment texts.
Historical reports of these symptoms before 1800 span several distinct eras:
Ancient and Classical Antiquity
- Ancient India (c. 1000 BCE): The Ayurvedic medical treatise describes a condition called Kampavata (where Kampa means tremor and Vata refers to the internal bodily air/energy controlling movement). The texts explicitly document a disease causing tremors, lack of movement, drooling, and a distinct posture. Remarkably, it was treated with the seeds of Mucuna pruriens, a tropical legume naturally rich in levodopa—the same active chemical used in modern Parkinson’s medication.
- Ancient Egypt (c. 12th Century BCE): A papyrus from the 19th Dynasty references a prominent non-motor symptom of advanced age and neurological decline, explicitly describing a king “drooling with age.”
- Galen of Pergamon (129–c. 216 CE): The famous Roman physician provided the most sophisticated classical analysis of the disease. He explicitly distinguished between different types of tremors, specifically describing tremor coactus—a tremor that occurs only when the limbs are at rest—as well as postural changes and muscle paralysis.
The Renaissance and Early Modern Era
Following Galen, unambiguous descriptions of Parkinsonian symptoms faded from medical literature for centuries, though they occasionally surfaced in the observations of prominent artists, thinkers, and playwrights.
- Leonardo da Vinci (1452–1519): In his private notebooks, Leonardo recorded a highly accurate observation of what we now know as involuntary rest tremors and loss of motor control, writing about “paralytics… who move their trembling limbs such as the head or the hands without permission of the soul; which soul with all its power cannot prevent these limbs from trembling.”
- William Shakespeare (1564–1616): While not a medical text, characters in Shakespeare’s plays frequently describe the physical realities of aging and infirmity. For example, in Henry VI, Part 2, the character Dick the Butcher describes the historical figure Say as having “a shaking palsy” that makes his head wag, capturing the prominent public visibility of the condition.
- Nicolas Poussin (1594–1665): The French classical painter suffered from a progressive, severe tremor in his later decades. Modern digital analyses of his brushstrokes from the 1620s through the 1660s show a calculated, gradual decrease in movement velocity and precision, matching the progressive nature of the disease.
The 17th and 18th Century Enlightenment
In the generations leading up to James Parkinson’s landmark essay, European physicians began identifying and naming specific motor characteristics of the condition with clinical precision.
- Franciscus Sylvius (1614–1672): This Dutch physician expanded on Galen’s work by formally distinguishing between “action tremors” (tremors that happen during voluntary movement) and “rest tremors” (tremors that happen when the body is supported and relaxed). Rest tremor remains a primary cardinal sign used in modern diagnoses.
- Ferenc Pápai Páriz (1649–1716): A Hungarian physician whose 1690 medical handbook Pax Corporis is widely considered by modern historians to be the first European document to successfully compile all four cardinal motor signs of Parkinson’s—tremor, rigidity, bradykinesia (slowness of movement), and postural instability—into a single description.
- Johannes Baptiste Sagar & Hieronymus David Gaubius (18th Century): Both physicians independent of one another documented a peculiar gait abnormality they called scerotyrbe festinans. They noted that when some patients attempted to walk at a normal pace, an involuntary shift in their center of gravity forced them to rapidly accelerate into a running pace to keep from falling forward. This is known today as a “festinant gait.”
- John Hunter (1728–1793): The renowned Scottish surgeon delivered a lecture in 1776 detailing a patient, Lord L-, whose hands were in constant, involuntary motion while awake but became perfectly still and at rest the moment he fell asleep—a hallmark feature of the Parkinsonian rest tremor.
Prior to 1800, these symptoms were viewed as separate, independent ailments rather than a unified neurodegenerative condition. James Parkinson’s true breakthrough in 1817 wasn’t discovering these individual symptoms, but realizing they all belonged to the exact same disease.
LOL, I wasn’t advocating that PD didn’t exist before 1800. I was pointing out that there is a view out there that that is exactly the case, and that it was caused by industrial toxins (I seem to recall that was Antoine’s view WHICH I ARGUED AGAINST). My point here was that if you believe as Antoine does that PD is mostly a post 1800 phenomenon, then you can’t at the same time hold the view that PD is a phenotype of brain aging, because you’d be in the absurd position of arguing that the brain didn’t age much before 1800. You can’t have it both ways. FWIW, my own view is that PD is a highly heterogenous disease, not any phenotype of an aging brain. It is further complicated by imprecise grab bag definitions based purely on symptoms like the example of “PD” caused by a street drug in LA that happened to kill substantia nigra cells resulting in PD-like symptoms. But that is not PD, because the causative mechanism is very different from physiological PD pathology like alpha-syn accumulation etc. in classic PD destruction of substantia nigra cells. The same for some more acute or more prolonged exposure to enviromental toxins like pesticides etc.
That is why I advocate focusing on specific pathology and not word games and definition shifting. If we are going to find treatments for as heterogenous a disease as PD, it will be by looking at those mechanisms, not stretching definitions and analogies to the breaking point.
My argument is that ageing is a failure of the genome to function at an adequate level and is an extension of development.
The reasons for that are that the mtDNA gets damaged so that citrate export is reduced and acetylation of nuclear proteins is reduced.
Because there is a form of homeostasis of mtDNA in any one cell through selective mitophagy this can be resisted to some extent also mtDNA can be protected. However, at a point the mitophagy machinery fails (this often results in the fission-mitophagy-fusion process stopping after fission) and then the cell will fail more substantially.
Hence anything that causes additional mtDNA damage will accelerate this process. Industrial toxins have the potential to do this. I have not done a search on this as it seems to be to be obvious that a subset of toxins will cause mitochondrial damage.
There are, therefore, a number of reasons why PD may be more common:
a) People survive other diseases and war, violence, accidents etc.
b) There are some serious toxins around that cause greater mtDNA damage
c) The mtDNA germline has deteriorated on an average basis.
d) Other reasons that I have not thought of yet, but if you ask me I will give this some thought.
None of this is word games or definition shifting. Instead it is a quite precise mechanism. It is a useful debate to have, however.
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FYI:
Parkinson’s disease: A 2024 two-sample MR (PMC11499214) found associations between galectin-3 and Parkinson’s disease risk.
See full thread here: Three Proteins in Your Blood Predict How Fast You're Aging. Here's What You Can Do About It - #8 by RapAdmin
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Fourteen trial arms from 12 unique studies (n ≈ 64,000; follow-up 7–50 months) were included. Two arms were excluded from pooled analysis due to zero events in both groups. The pooled OR for PD was 0.55 (95% CI: 0.27–1.12; p = 0.20). Heterogeneity was negligible (I2 = 0%), and the prediction interval ranged from 0.23 to 1.50. Subgroup analyses showed no significant effect for individual agents: empagliflozin 10 mg (OR 0.64, 95% CI 0.17–2.43), empagliflozin 25 mg (OR 0.33, 95% CI 0.01–8.15), dapagliflozin 10 mg (OR 0.33, 95% CI 0.09–1.23), sotagliflozin (OR 0.25, 95% CI 0.03–2.24), canagliflozin 100 mg (OR 3.00, 95% CI 0.31–28.81), and bexagliflozin (OR 1.50, 95% CI 0.06–36.99). No evidence of publication bias was detected (Egger’s p = 0.96).
I wouldn’t expect clinical trials to find anything but directionally dapagliflozin looks interesting.
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Yes, interesting, but looks like dose dependency might give us a clue? For empa, the low dose 10mg gives 0.64 vs 0.33 for 25mg. Then there’s the weird cana 3.0. But all the CI are nutty at the high end. Directionality? At least you could say there is some indication if escalating the dose gets you better OR, means it’s doing something, no?
Aging Immune Networks Linked to Parkinson’s Progression
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UCSF
We uncover AGTR1 as a key regulator of α-synuclein transcription and aggregation in human iPSC-derived mDA neurons, and AGTR1 inhibition as pro-survival in human iPSC-derived 2D and 3D neurodegenerative models of mDA neurons. These findings position inhibition of AGTR1 as a promising therapeutic strategy for PD neuroprotection.
When testing the neuroprotection of another widely used AGTR1 inhibitor, Telmisartan, we observed that it did not match that of Candesartan or Valsartan. Specifically, in 2D cultures exposed to CBE, Telmisartan appeared to have a detrimental effect on neuronal survival (Fig. S10A). In contrast, it showed a dose-dependent protective effect against rotenone-induced toxicity at higher concentrations (≥ 50 µM; Fig. S10B). Notably, in the 3D model, telmisartan exhibited one of the most robust protective effects against rotenone among the sartans tested (Fig. S10C–E). It is worth noting that, in addition to inhibiting AGTR1, telmisartan also acts as a partial agonist of peroxisome proliferator-activated receptor gamma (PPARγ). These discrepancies may reflect this property of telmisartan. Tolerance of telmisartan differs between 2 and 3D systems, with long-term exposure in 2D cultures potentially leading to increased toxicity, while the 3D assembloid model may better buffer such effects. Alternatively, telmisartan may exert context- or stressor-specific effects (e.g., preferential protection against mitochondrial stress induced by rotenone). These observations require further mechanistic investigation to better understand the differential effects of sartans on mDA neuroprotection.
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Wow, great find. And again, we see the problematic nature of using mice as models in PD - from the paper:
“Comparative snRNA-seq analysis of human and mouse brains revealed species-specific differences. In humans, the PD-vulnerable TH⁺SOX6⁺CALB1⁻ DA neuron subtype expressed AGTR1 but not AGTR2, whereas the corresponding mouse population lacked AGTR1a/b and expressed AGTR2 (Fig. S2C-D; Fig. S3C-D). Given AGTR1’s pro-degenerative role and AGTR2’s neuroprotective role in DA neurons [35], these differences highlight the limitations in using mouse models to study AGTR1-mediated mechanisms, emphasizing the value of human-based in vitro platforms.”
“Additionally, the source of Renin in the brain has been subject to controversy. While mouse brain cells show little to no Renin expression [24], human Renin expression is found in the Choroid plexus and MSN neurons. Human SNpc astrocytes express AGT, the precursor to AGTR1’s ligand, and our human mDA platform, incorporating neuron-glia interactions, mirrors these human-specific RAAS dynamics, particularly the AGTR1-AGT axis in the nigrostriatal pathway. While it is encouraging that similar findings have been found in mice models where MPTP-induced increase of α-Syn aggregation was mitigated by sartans and in AT1-KO mice [56] we believe that our findings highlight the need for human in vitro models to identify neuroprotective strategies that accurately reflect PD pathogenesis and ensure therapeutic relevance.”
It is always interesting to see how these agents are with regard to BBB penetration. Interesting - from the paper:
“While candesartan exhibits better BBB permeability than other sartans, its brain penetration remains suboptimal, as evidenced in a recent clinical trial [78].”
Looking at the 2D/3D issue I come back to something that I’ve been mulling over on and off for quite some time - is it just completely insane to use more than one ARB at the same time, adjusting the doses not to exceed a combined max? So for example in this context candesartan for 2D and telmisartan for 3D.
I was thinking about ARB combos for telmisartan + olmesartan, because olmesartan does not cross the BBB (and notably they did not test olmesartan in this paper). But then again, despite not crossing the BBB, olmesartan is associated with robust lowering of dementia risk (even better than telmisartan). My main fascination with olmesartan is that it’s more effective for BP lowering and uniquely lowers ACM.
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This is a trash Chinese team, institution, model, and publication - so, all around trash. But they are harping on lycopene, which has been identified before in the context of PD, so just in case there’s any fire in all this smoke, I’m posting this. FWIW, I already have been supplementing with 20mg lycopene daily #kitchen-sink.
CAUTION: likely trash!
Neuroprotective Effects of Lycopene in Parkinson’s Disease Mice: Potential Modulation of DAT/SLC6A3-Mediated Dopaminergic Pathway
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First I’ve heard of CO2 inhalation as a treatment for any neurodegenerative condition. I’m always ready to be surprised.
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Well, this is not a shock at all. First of all, targeted hypoxia is a well known intervention in NDD conditions, which is what CO2 is doing as one modality. But also there is the well known fact that cigarette smoking is associated with beneficial effects on PD. For a long time people thought it must be the nicotine, but that never panned out in multiple attempts, and more recently researchers have focused on the CO2 component of cigarette smoking - there’s your inhalation! - and the resulting transient mild hypoxia. Bottom line, far from being in some way new and exotic, CO2 in the context of NDD amelioration has a long history and is an active area of research.
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So hypercapnia occurs in type 2 respiratory failure, you don’t have to be hypoxic. Cigarette smoking does result in increased carbon monoxide, not carbon dioxide with is what is the issue with hypercapnia. The problem is that one can get CO2 narcosis and stop breathing - we see if in the ER and ICU with some frequency.
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Researchers have reported that inhibition of 15-hydroxyprostaglandin dehydrogenase was shown to protect neurons and improve motor function in mouse models of Parkinson’s disease in findings that could support repurposing of drugs currently under development
Full paper that is the subject of this writeup:
Inhibiting 15-PGDH restores redox homeostasis and confers neuroprotection in Parkinson’s disease
https://www.sciencedirect.com/science/article/pii/S2213231726002843?via%3Dihub
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Leucine and whey?