Treatment with the bile acid, UDCA, has been reported to have a wide variety of effects that are compatible with extended lifespan in mammals, including protecting against metabolic derangements such as diabetes, and suppression of tumor formation (Oyama et al., 2002; Lukivskaya et al., 2004). Nevertheless, no previous lifespan studies have been reported for UDCA. At the dose used in this study, there were significant reductions in body weight across the lifespan in both male and female mice, suggesting that UDCA treatment had biological or physiological effects. However, there was no effect of UDCA on median or maximal lifespan in either sex. Given the wide range of positive effects reported for UDCA on measures of healthspan, it is unclear why it had no effect on lifespan. It is possible that higher or lower doses of UDCA may be effective. On the other hand, as we observed with NDGA in the present study, the effects of specific interventions on lifespan may be distinct from effects on age-sensitive physiological changes in specific organ systems.
They used 5,000 ppm = 833 mg/kg (mice) => ~67 mg/kg in humans (HED). So, about 5 g/day for the average adult. That’s twice the dose used in the upcoming PD trial (2.5 g/day). The normal dose for gallstones is about 10 mg/kg, typically 750 mg/day (DDD, according to the WHO).
Hopefully, I’ll soon receive Ora Biomedical’s results for UDCA. In any case, if one has elevated AST, ALT, ALP, GGT, UDCA seems like a safe bet.
I am going to the Parkinson’s meeting in London tomorrow and if antoine is there we can meet. I did a bit of research on Parkison’s recently and it does seem to have some links to aberrant splicing which makes it in many ways a normal disease of aging that may require some particular alleles.
@John_Hemming and I attended the research meeting where the principal investigator behind the exenatide trial detailed the results. tl;dr: it failed in every single subgroup they looked at. They’re still doing some analyses on CSF with some hope that patients who got more exenatide into their brain had better outcomes, but overall, it’s a total failure.
My guess: dulaglutide and lixisenatide might not do much better. I think if HbA1c isn’t lowered (and apparently exenatide barely lowered that marker during the trial) then you can’t expect anything. So semaglutide might work. There are ongoing trials in AD and PD so we’ll soon (2027?) know.
If you are not actually improving blood sugar handling then you should not expect an improvement in parkinsons. This, of course, raises two questions
a) would the dysregulation of blood sugar (temporary) from Rapamycin argue against the use of Rapamycin for parkinsons. (or argue for very intermittent usage).
b) would activity to improve glycemic control in non diabetics improve Parkinsons.
Antoine and I had a useful discussion with the people at the event.
High-dose metformin is associated with a higher rate of PD. So, glycemic control is insufficient and should not come at the expense of mitochondrial health. That’s why SGLT2i seem interesting in PD: glycemic control + mTOR inhibition (see Figure 1 here). But they’re mild.
However, what’s interesting is that many Parkinson’s patients report that their symptoms improve (or totally stop) at high altitudes (including in an airplane). So, in a HYPObaric environment. There’s an ongoing trial for that.
Interventions will be conducted three times a week, for four weeks in total.
five times five minutes hypoxia interspersed with five minutes of normoxia, totaling 45 min
The thing is that it is the reduction in partial pressure that does the job of starting HIF 1 alpha. That can be done at a normobaric pressure, but starting with a higher concentration of Oxygen. I do this using an Oxygen concentrator.
Independent of its function as a precursor for DA synthesis, we demonstrated that l-DOPA can mediate both, a neurotoxic and a neuroprotective activity. Interestingly, the precise kind of action depends directly on the oxygen tension. Under normoxic oxygen levels, auto-oxidation of l-DOPA and linked ROS production prevails, while under hypoxic conditions l-DOPA auto-oxidation is heavily reduced.
So overall our data suggest an oxygen-dependent dual effect of l-DOPA: Under normoxic conditions l-DOPA auto-oxidation produces cytotoxic ROS, whereas under hypoxia and during shorter treatment duration l-DOPA is more stable and the ROS scavenging capacity prevails. Moreover, we observed that neuronal cell lines were much more vulnerable than other human cell types to l-DOPA-mediated ROS.
Oxygen partial pressure will be an issue, but specifcially in getting the HIF 1 alpha nuclear factor initiated it is the change in pressure that makes an issue.
You wrote “At this point I will assume that switching on HIF from time to time is “a good thing”. Therefore, we need to know how to switch on HIF.” So I’m putting these here without context:
More and more we’re finding the importance of the gut biome to the immune system. This latest information on gut biome and Parkinson’s might be of interest to some people.
The fix might be as simple as increasing certain vitamins and supplements like B2 and B7. On a similar vein, for decades ulcers were treated with surgeries that did not prevent the reoccurrence.
We realize that treating with antibiotics can cure certain ulcers. You don’t hear about ulcers the way you use to.
No relationship was observed between dairy consumption (HR 1.07, 95% CI 0.82–1.39), individual dairy products (milk: HR 0.95, 95% CI 0.73–1.23; yogurt: HR 1.03, 95% CI 0.82–1.29; cheese: HR 1.13, 95% CI 0.85–1.51), or vitamin D (HR 1.08, 95% CI 0.80–1.45) with PD risk. However, we observed a risk-increasing association with higher calcium intakes (HR 1.33, 95% CI 1.00-1.78, p for trend = 0.031), which was more pronounced in men (HR 1.50, 95% CI 1.00-2.25, p for trend = 0.044) and in ever smokers (HR 1.64, 95% CI 1.06–2.53, p for trend = 0.014). No compelling evidence was found for an association between dairy products or vitamin D intake and PD risk indicating a potentially limited relevance of dairy intake in PD risk than previously described. Our observations of a positive association between dietary calcium intake and PD risk in men and in ever smokers require further validation.
This suggests that vitamin D may not be related to the development of PD and that other mechanisms might therefore be responsible for the results in the aforementioned studies on serum vitamin D levels. One Mendelian randomization study explored the association between genetically decreased 25-hydroxyvitamin D concentrations with PD in individuals of European descent from 15 cohorts to investigate a potential causal relationship. The authors concluded that there is a lack of definite evidence supporting a role of vitamin D in PD.
On the other hand, men at risk of PD might prefer to avoid dairy products:
This suggests that vitamin D may not be related to the development of PD and that other mechanisms might therefore be responsible for the results in the aforementioned studies on serum vitamin D levels. One Mendelian randomization study explored the association between genetically decreased 25-hydroxyvitamin D concentrations with PD in individuals of European descent from 15 cohorts to investigate a potential causal relationship. The authors concluded that there is a lack of definite evidence supporting a role of vitamin D in PD.
I think the key role of Vitamin D is to maintain the bodies optional systems that only function when there is more food available. Hence the VDR enables optional genes. These may help with lot of things, but do not prevent diseases of aging.
I think it is clear that PD is a disease of aging as it occurs with age. I start then with the assumption that there is a problem with certain proteins being produced probably as different splices when power levels in the cells go down.
If it is a splicing issue (and there is evidence for this) that would explain a variation between people are different alleles will result in different splices at lower levels.
Hence although I think Vitamin D is someone to keep at a high serum level I don’t think it is an anti-aging vitamin per se.
I know identical twins, age 80. Both have severe arthritis.
One has been on methotrexate and its predecessors for 10-20 years and is mentally sharp. The other was diagnosed with fronto-temporal dementia 5 years ago.
Confounders: twin with dementia was much more sedentary, ate poorly, had untreated hyper-cholesterolemia, had a heart attack in late 40s, had children much later in life, was less social.
