7 replies to this topic

[jwilcox25]

Seems to be conflicting info on this.  Trying to understand pros/cons of metformin supplementation in healthy individuals.  There are studies suggesting it increases Alzheimer's/dementia risk, but that may be due to B12 deficiency (which can be avoided thru B12 supplementation).  On the other hand, AMPK activation itself may contribute to Alzheimer's.

 

AMPK activation detrimental

AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress
   in vitro study. metformin / AICAR > inhibit axogenesis, axon growth [proportional to AMPK activation]

 

CAMKK2-AMPK Kinase Pathway Mediates the Synaptotoxic Effects of Aβ Oligomers through Tau Phosphorylation

   mouse study. + intracellular Ca2+ -> dendritic spine loss.  block AMPK -> protects hippocampal neurons against AB42 and prevents dendritic spine loss

 

Metformin detrimental

Metformin treatment increases mRNA levels of inflammatory factors and decreases mRNA levels of neurotrophic factors in brains of C57BL/6 mice
   mouse study. metformin -> + mRNA of inflammatory no cognitive impact
 

Metofmrin no effect
Metformin Supplementation and Life Span in Fischer-344 Rats
   rat study. metformin -> ~ mean life, ~ max life
   but also no glucoregulation

 

Metformin positive

Metformin improves healthspan and lifespan in mice
   mouse study -> +4-6% mean life, ~ max life

[Darryl]

The research is conflicting.

 

AMPK activation protective:

 

Vingtdeux V et al. 2011. Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation. The FASEB Journal, 25(1), pp.219-231.

Kodiha, M. and Stochaj, U., 2011. AMP kinase-the missing link between type 2 diabetes and neurodegenerative diseases?. Trends Mol Med.

Greco SJ et al. 2011. Leptin boosts cellular metabolism by activating AMPK and the sirtuins to reduce tau phosphorylation and β-amyloid in neurons. Biochemical and biophysical research communications, 414(1), pp.170-174.

Kim E et al. 2012. AMPK γ2 subunit gene PRKAG2 polymorphism associated with cognitive impairment as well as diabetes in old age.Psychoneuroendocrinology, 37(3), pp.358-365.

Wang ZG et al. 2015. AMPK-dependent autophagic activation is probably involved in the mechanism of resveratrol exerting therapeutic effects for Alzheimer's disease.Rejuvenation research, 18(1), pp.101-102.

Kornelius E et al. 2015. DPP‐4 inhibitor linagliptin attenuates Aβ‐induced cytotoxicity through activation of AMPK in neuronal cells. CNS neuroscience & therapeutics, 21(7), pp.549-557.

 

AMPK activation pathological:

 

Lopez-Lopez C, 2007. Disturbed cross talk between insulin-like growth factor I and AMP-activated protein kinase as a possible cause of vascular dysfunction in the amyloid precursor protein/presenilin 2 mouse model of Alzheimer's disease. The Journal of neuroscience, 27(4), pp.824-831.

Vingtdeux V et al. 2011. AMPK is abnormally activated in tangle-and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies. Acta neuropathologica,121(3), pp.337-349.

Salminen A et al, 2011. AMP‐activated protein kinase: a potential player in Alzheimer’s disease. Journal of neurochemistry, 118(4), pp.460-474.

Park H et al. 2012. Neuropathogenic role of adenylate kinase-1 in Aβ-mediated tau phosphorylation via AMPK and GSK3β. Human molecular genetics,21(12), pp.2725-2737.

Mairet-Coello G et al. 2013. The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through Tau phosphorylation.Neuron, 78(1), pp.94-108.

Mairet-Coello G. and Polleux F., 2014. Involvement of ‘stress–response’kinase pathways in Alzheimer's disease progression. Current opinion in neurobiology, 27, pp.110-117.

 

It can, of course, be both. Aβ aggregates activate AMPK, and while this creates other cellular stresses, it also activates the autophagy that helps clear Aβ.

 

Son SM et al. 2012. Aβ-induced formation of autophagosomes is mediated by RAGE-CaMKKβ-AMPK signaling. Neurobiology of aging, 33(5), pp.1006-e11.

 

WHY would Aβ activate AMPK? If this is adaptive, perhaps its an evolved defense pathway against Alzheimer's-like pathologies in early life, when AD would affect reproductive fitness, which works so long as autophagy does. As lysosome efficiency declines with age, all the Aβ aggregates just accumulate, causing fruitless AMPK activation.

 

AMPK activation plays a role in other neurodegenerative diseases too:

 

Ju TC et al, 2014. AMPK-α1 functions downstream of oxidative stress to mediate neuronal atrophy in Huntington's disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1842(9), pp.1668-1680.

Xu Y.et al., 2014. Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson's disease.Cellular signalling, 26(8), pp.1680-1689.

 

AMPK has protective effects against aging pathologies in so many other instances that we can't say its bad, on the other hand one can have too much of a good thing.

 

There's a Scylla and Charybdis conundrum in a lot of anti-aging interventions: reduce nutrient/growth signalling enough to inhibit cancer, stem-cell exhaustion, and induce autophagy, while retaining enough growth signalling to prevent muscular and neural atrophy. Worse still, the goal posts appear to move as one progresses through life, with reduced nutrient signalling (AMPK activation) being beneficial in early and mid-life, but much less so in the elderly.

 

 

 

Edited by Darryl, 01 February 2016 - 12:03 AM.

[xEva]

I find it strange that a positive/negative attributes are attached to an enzyme. Even if it is usually activated by low nutrients or starvation, it cannot be beneficial or detrimental by itself.

..though I understand the pharma approach: kinda identify an enzyme and block it if it's "bad". But really, it seems so primitive. It's akin to jamming one of the weals in a complex mechanism in hopes of -- what? One should hope such an intervention would not break the thing entirely.

It's just and enzyme. A peg in a clockwork.

[jwilcox25]

Darryl - given you have studied this in depth and have discussed supplementation in other threads, what is your latest personal conclusion in terms of supplementing metformin (or other AMPK activators) vs not?  How do you think about risk/reward?

 

And given your point on interaction w/ age, would that change if you were 30, 50, 70 years old?

Edited by jwilcox25, 01 February 2016 - 01:58 AM.

[corb]

 

Seems to be conflicting info on this.  Trying to understand pros/cons of metformin supplementation in healthy individuals.  There are studies suggesting it increases Alzheimer's/dementia risk,

 

Could be any number of things:

1.The outdated way medicine looks at neurodegenerative disorders - there's multiple types of dementia, much more than we've named at present, but regardless medicine keeps to it's umbrella terms instead of admitting Parkinson's and Alzheimer's are syndromes instead of diseases.

So it's quite possible for a researchers to find that a molecule is protective and detrimental at the same time - they may not be looking at the same disease in reality.

 

2.It's possible that the stage of the disease can have an affect on cellular chemistry and metabolism so a protective molecule becomes a detrimental one when the disease progresses.

 

3.The genetically modified animal models they use to study neurodegenerative diseases can be a bad analogue for actual disease progression.

 

4. And then come the more typical reasons - science comes down to interpretation of results, maybe one side of the "argument" is interpreting the results wrong.

 

Since we're so clueless when it comes to these diseases and how to treat them at present it's quite hard to say with certainty.

[Darryl]

Darryl - given you have studied this in depth and have discussed supplementation in other threads, what is your latest personal conclusion in terms of supplementing metformin (or other AMPK activators) vs not?  How do you think about risk/reward?

 

And given your point on interaction w/ age, would that change if you were 30, 50, 70 years old?

 

Not as much depth as it merits. I think AMPK activation is an important part of the benefits of caloric restriction, fasting, exercise, metformin, telmisartan, berberine, salicylates, α-lipoic acid, and dietary compounds including resveratrol, curcumin, anthocyanins, EGCG, genestein, capsaicin (among others) in models of aging. Some reduce fuel, some exhaust ATP, some are mild respiratory complex I poisons, some induce mitochondrial uncoupling (acting like 2,4-DNP and possibly C₆₀) to reduce both ATP and superoxide production. Given my knowledge of adverse effects, all but 2,4-DNP and berberine appear fairly safe, taken in isolation, under adverse effect surveillance / medical supervision, at prescribed or near dietary doses. What happens when we hopefuls hammer this pathway a dozen ways at once isn't known.

 

This review isn't a bad introduction to potential benefits of AMPK activation:

 

McCarty MF, 2014. AMPK activation—protean potential for boosting healthspan. Age, 36(2), pp.641-663.

 

Personally, I'm in my 40s and practice intermittent fasting (3 days, once per month), much too intermittent exercise, and target AMPK with metformin (2 x 500 mg), magnesium salicylate (2 x 467 mg) and curcumin. I took berberine as OTC metformin until recently, but became concerned with possible and plausible DNA breaks.

 

The comment about changing goalposts was less in reference to AMPK than to the declining benefit of protein restriction (which targets mTOR just downstream of AMPK) seen around age 65-70 in this study:

 

Levine ME et al. 2014. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell metabolism, 19(3), pp.407-417.

 

I can think of several hypotheses why protein restriction loses its glint around retirement, I suspect a main one is that with lower activity and overall caloric intake, restricted protein diets fall to levels that interfere with immune response. Again Scylla and Charybdis: low nutrient/growth signalling may prevent prevent premature immune senescence, but you still need enough to fight infection. Similar arguments apply to muscular or cognitive frailty.

Edited by Darryl, 01 February 2016 - 12:53 PM.

[jwilcox25]

Thanks - really helpful to understand how you are approaching it personally.  I need to spend more time on the biochemistry on AMPK, but given the conflicting evidence on that front, it seems better to rely on long-term human/mammal studies on the specific compound eg metformin.  The problem is that all the available human studies are all on diabetes obviously, which confounds everything, given the disease affects the same endpoints we care on.  Are there any studies on normal mammals that showed improvement or lack of harm to congition/brain?

Edited by jwilcox25, 02 February 2016 - 12:10 AM.

[SearchHorizon]

Looking at some papers, the apparent contradiction in metformin's effect appears to be with the location of its administration.

 

When AMPK is activated overall (e.g., muscle + brain), the effect has been positive - increased sensitivity to sugar, fat loss, glucose reduction.  In contrast, when AMPK is activated in brain cells (without activating AMPK in other tissues), the subjects (l.e., mice) gained weight and suffered other issues.

 

The only thing I'd be careful about taking metformin for health purposes (at least in theory), I'd space apart the administration of metformin (e.g., once every 3 days). Metformin mimics metabolic stress, and this means, one could be triggering cellular mechanisms that require adaptive response.  

 

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I know that a study or two suggested that metformin may inhibit telomerase. I wonder, however, if such study looked at the downstream effects of metformin. Given that it is an AMPK activator, it can be viewed as an "exercise" mimic.  

 

An exercise generally activates AMPK, which then inhibits telomerase (at least in T cells according to one study). Despite this, however, exercise elevates telomerase. I suspect that one of metormin's downstream effects in vivo (as the result of the body's adaptive response) is to activate telomerase, although its immediate effect, like exercise, is to inhibit telomerase via AMPK.

 

 

 

 

 

 

Edited by SearchHorizon, 06 June 2016 - 05:36 AM.