6 replies to this topic

[Michael]

All:

There is a significant amount of very preliminary research suggesting that the diabetes drug metformin might be a CR-mimetic anti-aging drug, counterbalanced chiefly by a study that found that metformin did not extend lifespan in healthy, normal rats, altho' the results were ambiguous. One worry about long-term untested use in healthy, nondiabetic humans was a study that seemed to suggest that metformin might accelerate production of the Alzheimer's disease aggregate, beta-amyloid. (This latter study was well-discussed in the posts starting here one thread, and also in another I can't find). At the same time, an even more preliminary study seemed to suggest that metformin might slow down the very earliest stages of tau aggregate formation. A new, apparently short-term study, presented at the 2011 Neuroscience Meeting by Rafal de Cabo (who is running one of the two (apparently) well-done lifespan studies in normal mice) and colleagues, seems to offer some reassuring evidence on the beta-amyloid question, along with a lack of phenotypic effect, while still raising some concerns about its effects on brain health in the long term:

Several studies have shown impaired cognition and memory performance and an increased risk for developing Alzheimer’s disease with type-2 diabetes. With this apparent relationship, it is important to understand the impact of commonly used insulin sensitizing and anti-diabetic agents on brain chemistry and function. This study investigates the effects of the highly prescribed anti-diabetic agent, metformin, on learning and memory, neurochemistry and neurohistology ... In the first part of this project, we used behavioral testing, quantitative RT-PCR, and western blot analyses to assess the effects of metfomin on C57BL/6 mice fed with standard diet or high-fat diet. The second part of this project ... determine[d] the effects of metformin treatment on Alzheimer’s type pathology in the APP+/PS1+ double transgenic (dtg) mouse model of Alzheimer’s disease.

As assessed by performances in the Morris water maze test of hippocampal based memory function, metformin treatment had no significant effect on spatial memory or learning. Quantitative RT-PCR on whole brain homogenates revealed that metformin treatment led to decline in mRNA levels of several neurotrophic factors including brain-derived neurotrophic factor, nerve growth factor and neurotrophin factor-3. Additionally, metformin treatment increased mRNA levels of key inflammatory factors including tumor necrosis factor alpha, Interleukin -6 and Interleukin-10.

In [the Alzheimer’s-model mice], metformin treatment showed no effect on beta-amyloid plaque deposition or on the number of doublecortin labeled, newly developing neurons in the hippocampus.

Overall, these data suggest that although metformin is an extremely effective treatment for the deleterious changes that occur in peripheral systems with type-2 diabetes, its effects may not extend significant benefits in brain chemistry and function and may increase susceptibility to damage.(1)

If I'm reading this right, these were relatively short-term studies, and it doesn't sound as if they did behavioral studies on the AD mice. I think it is of concern that the drug upregulated brain inflammatory mediators and depressed expression of neurotrophic factors, which might lead to a human responding more poorly to the many tiny insults that slowly ravage the aging brain over time, raising the inflammatory response excessively while failing to provide protective and anabolic response to neurons under stress. The apparent lack of effect on production and/or survival of new neurons seems reassuring, but it might just be that the effect is swamped by the beta-amyloid -- and certainly, it seems not to have offered any protection against the insult of the disease. And unfortunately, this model of the disease does not lead to neuronal loss, so there's no way to assess what the effects are on survival of existing neurons.

These mice don't develop tau pathology, so there is no further information one way or the other on any protective effect on that front. While one could spin out scenarios under which early activation of inflammatory responses might help microglia to clear out more early plaque, there was (again) apparently no such protection in the AD mice.

Overall, somewhat worrisome.

References
1. J. S. ALLARD, K. SANKAVARAM, E. PEREZ, R. MINOR, R. DE CABO. Presentation Title: Metformin treatment increases mRNA levels of inflammatory factors and decreases mRNA levels of neurotrophic factors in brains of C57BL/6 mice. Program#/Poster#: 98.04/WW42. 2011 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2011. Saturday, Nov 12, 2011, 4:00 PM - 5:00 PM. Online.

[mikeinnaples]

It seems mostly worthless research to me in deciding whether or not to take metformin, especially considering that this is quite literally a needle in a haystack of positive research data.

Not only that, this is a bit misrepresentitive of you: metformin might accelerate production of the Alzheimer's disease aggregate, beta-amyloid . The research itself showed that the beta-amyloid was only accelerated in absence of insulin. In the presence of insulin, it was actually decreased from the controls. See the attachment.

http://www.longecity...&attach_id=8316

Edited by mikeinnaples, 21 February 2012 - 01:46 PM.

[Michael]

It seems mostly worthless research to me in deciding whether or not to take metformin, especially considering that this is quite literally a needle in a haystack of positive research data.

A haystack of positive data much of which is of questionable relevance (studies in diabetics, non-mammalian species, and cancer-prone mice), and none of which has properly addressed this question of effects on brain aging. I think that makes it rather significant

Not only that, this is a bit misrepresentitive of you: metformin might accelerate production of the Alzheimer's disease aggregate, beta-amyloid . The research itself showed that the beta-amyloid was only accelerated in absence of insulin.

Right: I agreed with the cogency of these points about the earlier study, which is why I specifically linked to your previous posting of them . The new study is in vivo, and (as I said) seems to find no effect on Aβ, albeit with the limitations of the model. However, as noted, there are other changes that occurred, even in normal mice, that are of concern.

[mwestbro]

I wonder what the results would be if the metformin mice received enough B12 to compensate for the poor B12 absorption induced by metformin. Or some additional calcium, which also helps correct the problem (although I admit that it has always seemed like a roundabout way to handle it to me--why not just give the B12?).  cv800.pdf   52.19KB   7 downloads

Edited by mwestbro, 21 February 2012 - 05:16 PM.

[mikeinnaples]

Not only that, this is a bit misrepresentitive of you: metformin might accelerate production of the Alzheimer's disease aggregate, beta-amyloid . The research itself showed that the beta-amyloid was only accelerated in absence of insulin.

Right: I agreed with the cogency of these points about the earlier study, which is why I specifically linked to your previous posting of them . The new study is in vivo, and (as I said) seems to find no effect on Aβ, albeit with the limitations of the model. However, as noted, there are other changes that occurred, even in normal mice, that are of concern.

For what its worth, drinking water may cause death .

Edited by mikeinnaples, 21 February 2012 - 05:38 PM.

[mikeinnaples]

I wonder what the results would be if the metformin mice received enough B12 to compensate for the poor B12 absorption induced by metformin. Or some additional calcium, which also helps correct the problem (although I admit that it has always seemed like a roundabout way to handle it to me--why not just give the B12?).  cv800.pdf   52.19KB   7 downloads

I am not familiar enough with the B12 / AD link to comment, so I will refrain from commenting too much. However, I do have a question as to whether or not the research is pointing towards low B12 being causal or high B12 being preventative? I am siding with low B12 being causal. If so, that would definitely throw a wrench in some of the metformin studies in regards to AD. My quick glance through some research papers mention a link between blood homocysteine levels and AD as well. Metformin as been shown to increase homocysteine levels at least in diabetics compared to controls indirectly due to interfering with B12 and folate ( -14% B12 and - 7% folate compared to placebo). This whole issue with B12/Folate and homocysteine metabolism is an interesting consideration when talking about metformin's effect on the brain.

Thoughts on that Michael?

Edited by mikeinnaples, 21 February 2012 - 05:54 PM.

[Gerald W. Gaston]

Not only that, this is a bit misrepresentitive of you: metformin might accelerate production of the Alzheimer's disease aggregate, beta-amyloid . The research itself showed that the beta-amyloid was only accelerated in absence of insulin.

Right: I agreed with the cogency of these points about the earlier study, which is why I specifically linked to your previous posting of them . The new study is in vivo, and (as I said) seems to find no effect on Aβ, albeit with the limitations of the model. However, as noted, there are other changes that occurred, even in normal mice, that are of concern.

It as also mentioned here in the poll:

http://www.longecity...post__p__385496

Most type 2, esp early onset have higher insulin levels as they have insulin resistance.I fall into that category (although not near as hight now). I supplement with B12, have my T checked every 6 months and take 2G Metformin daily. My fasting numbers went from ~105 to 90 in 6 months.