Category Archives: Scientific Study

Resveratrol, Life Extension, PDE4 and CILTEP

A few years ago I attended the Transhuman Visions conference and I’ll be at RAADFest at the end of this week. The most popular topic that people spoke about at Transhuman Visions and what RAADFest is all about is unlimited lifespans and how to achieve them. In light of that, I’d like to take a detour from talking about cognitive enhancement, which has been the subject of my previous articles, and instead explore some recent research into nutritional strategies for healthy aging.

Resveratrol, a chemical that naturally occurs in red wine in small amounts has been touted for its purported health promoting and life extending properties. Despite a lot of initial enthusiasm, its health enhancing properties have only proven robust in studies where mice were fed a high fat diet. In these cases, it increased the high fat diet mouse’s life span such that it matched the lifespan of mice who were fed a calorie restricted diet. Calorie restriction is a well known mechanism for extending the life span of many mammals [1]. It should be noted that this diet with added resveratrol did not significantly increase maximum life span [2][3]. Nevertheless, extending so called health span, the period during which an organism remains healthy and active regardless of total life span, even when eating a less than ideal diet, remains a worthwhile goal that resveratrol may contribute to.

Resveratrol’s apparent health promoting activities were investigated by a number of studies. The early consensus on resveratrol seemed to be that it worked by activating beneficial SIRT1 genes that were also activated by calorie restriction [4][5]. The mechanism of action was originally thought to work via direct activation of SIRT1 [6]. Later it was shown that resveratrol did not directly activate SIRT1 but worked through an indirect mechanism [7]. This lead researchers to an indirect activator of SIRT1 known as AMPK which resveratrol activated. Resveratrol’s neuroprotective effect was theorized to be due to its activation of AMPK in neurons [8]. This lead researchers to ePAC1, an activator of AMPK. ePAC1 is activated by cAMP which is increased by PDE4. Thus this lead back to PDE4 inhibition being the mechanism of action of resveratrol. Indeed Rolipram, another well known synthetic inhibitor of PDE4, mimicked the apparent health benefits of resveratrol [9].

When PDE4 inhibition was uncovered as the mechanism of action of resveratrol’s health promoting effects there was discussion in the medical literature about how so many beneficial health effects lead back to PDE4 inhibition [10] and how PDE4 inhibition might be useful in treating age related diseases [11].

Given that components of the CILTEP stack have been shown in studies to increase cAMP by both inhibiting PDE4 via Luteolin contained in Artichoke Extract [12] and directly increasing cAMP via forskolin’s effects on adenylyl cyclase [13], it stands to reason that some of the mechanisms of action of resveratrol could theoretically apply to CILTEP. Especially since Luteolin has been shown to activate AMPK [14] and is a slightly stronger PDE4 inhibitor than resveratrol [15] [16].

The nootropic concept is that a drug or supplement can both improve cognition and be beneficial for health. In that sense PDE4 inhibition could be an outstanding nootropic as it possibly combines the best of both worlds given that research has demonstrated PDE4 provides substantial improvement in cognitive performance in mice [17] and it has now gathered a fair body of research literature, via resveratrol studies, that provide evidence for its possible value in maintaining health and longevity.

[1] Kemnitz JW. Calorie restriction and aging in nonhuman primates. ILAR J. 2011;52(1):66-77. PMID 21411859

[2] Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008;8(2):157-68. PMID 18599363

[3] Da luz PL, Tanaka L, Brum PC, et al. Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats. Atherosclerosis. 2012;224(1):136-42. PMID 22818625

[4] Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem. 2005;280(17):17187-95.PMID 15749705

[5] Bordone L, Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol. 2005;6(4):298-305.PMID 15768047

[6] Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425(6954):191-6. PMID 12939617

[7] Beher D, Wu J, Cumine S, et al. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des. 2009;74(6):619-24. PMID 19843076

[8] Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci USA. 2007;104(17):7217-22. PMID 17438283

[9] Park SJ, Ahmad F, Philp A, et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell. 2012;148(3):421-33. PMID 22304913

[10] Chung JH. Metabolic benefits of inhibiting cAMP-PDEs with resveratrol. Adipocyte. 2012;1(4):256-258. PMID 23700542

[11] Chung JH. Using PDE inhibitors to harness the benefits of calorie restriction: lessons from resveratrol. Aging (Albany NY). 2012;4(3):144-5.PMID 22388573

[12] Ko WC, Shih CM, Lai YH, Chen JH, Huang HL. Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships. Biochem Pharmacol. 2004;68(10):2087-94. PMID 15476679

[13] Seamon KB, Daly JW. Forskolin: a unique diterpene activator of cyclic AMP-generating systems. J Cyclic Nucleotide Res. 1981;7(4):201-24. PMID 6278005

[14] Liu JF, Ma Y, Wang Y, Du ZY, Shen JK, Peng HL. Reduction of lipid accumulation in HepG2 cells by luteolin is associated with activation of AMPK and mitigation of oxidative stress. Phytother Res. 2011;25(4):588-96. PMID 20925133

[15] Park SJ, Ahmad F, Philp A, et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell. 2012;148(3):421-33. PMID 22304913

[16] Ko WC, Shih CM, Lai YH, Chen JH, Huang HL. Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships. Biochem Pharmacol. 2004;68(10):2087-94. PMID 15476679

[17] Li YF, Cheng YF, Huang Y, et al. Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J Neurosci. 2011;31(1):172-83. PMID 21209202

Possible benefits of short-chain fatty acids (SCFAs) for optimizing weight loss and metabolism.

What are SCFAs and why are they important to human health?

Short-chain fatty acids (SCFAs) are produced in the gut by friendly bacteria. The main ones produced in the gut that are important in human health are butyrate, propionate, and acetate. The body processes these short-chain fatty acids, but they also interact with several systems in the body in unique ways that have beneficial effects on metabolism.

Why should we take them though? Don’t gut bacteria produce enough SCFAs by themselves? Many people don’t have healthy gut flora. They also might not get enough fiber in their diet. Also, by taking supplemental SCFAs, it’s also possible to take them in more substantial amounts than would typically be produced in the gut without consuming enormous amounts of fiber. Taking larger than average amounts of short-chain fatty acids can be useful for biohacking purposes such as enhanced weight loss.

Some Research on SCFAs

  • Oral administration of SCFAs could reduce fat gain in pigs via reducing fat storage and enhancing fat burning. Study
  • Butyrate and propionate protect against diet-induced obesity and regulate gut hormones. Study
  • Acute oral sodium propionate supplementation raises resting energy expenditure and fat burning in fasted humans.Study
  • Propionate. Anti-obesity and satiety enhancing factor? Study.

How I am taking them

  • Sodium Butyrate and Propionate Supplement:

  • Apple Cider Vinegar Supplement ( for increasing acetate ) :

Blinking Lights Used To Treat Alzheimer’s Disease In MIT Study. How Does This Even Work?

The Study

Recently, MIT released a study showing evidence that mice bred to have Alzheimer’s disease, when exposed to blinking LEDs at 40hz, had their amount of illness causing amyloid-beta protein reduced. The effect even worked in “Wild Type” mice that were not specifically bred to exhibit Alzheimer’s symptoms.  The effect prevented amyloid-beta build up in mice in the early stages of the disease, but it also reduced amyloid-beta protein in mice that had already accumulated significant amounts of the protein and were thus at a later stage of the disease.  This result seems hard to make sense of because flashing lights aren’t something that seems capable of having disease curing effects. How could this possibly work given the difficulty in treating neurodegenerative diseases?

Looking more closely at the study, specifically at the mechanism of action proposed by the researchers, we find increased microglial activity. The microglial cells are the primary immune system cells in the brain. Some theorize that infections cause Alzheimer’s in the brain, so according to that theory, increasing the activity of microglia could help fight a possible Alzheimer’s disease causing infection.  In the study, the specific observed activity of the microglia was an increase in engulfing of amyloid beta proteins.  The end products of degraded amyloid protein were also reduced.  This suggests that there was an alteration in endosomal processing.

When researchers blocked GABA receptors, the amyloid clearing effect no longer worked. Contradicting GABA receptor activation being the sole source of the amyloid-beta reducing effect is that in the past GABA agonists failed to improve Alzheimer’s patient’s outcomes.

Speculation

GABA receptors connect to microglia via astrocytes. Astrocytes modulate microglial activity, and their behavior is affected via GABA signaling. GABA acts as an anti-inflammatory via these cells. Strengthening the anti-inflammatory hypothesis is there is evidence that anti-inflammatories such as aspirin protect against Alzheimer’s pathology.

Astrocytes are related to circadian rhythm brain entrainment and Gamma oscillations. Flicking lights on and off increases glutamate signaling which is countered by GABA signaling from astrocytes. If GABA signaling doesn’t modulate glutamate signaling, that leads to the well known human photoparoxysmal response in people with epilepsy, in which blinking lights can cause seizures, perhaps because of sclerotic astrocytes that can’t function properly to slow down the elevated glutamate driven excitation.

So can we spin together a theory about how this all works? How do blinking lights reduce disease causing amyloid plaques?

My Speculation: Blinking lights cause astrocytes to get activated and release GABA to control photoparoxysmal driven glutamate signaling. This release, along with other signals from astrocytes, triggers anti-neuroinflammation and engulfing activity in microglia which helps clean up Alzheimer’s damage. Lack of effectiveness of GABA agonists alone in the treatment of Alzheimer’s disease provides evidence against the idea that GABA alone was solely responsible for the effect. Perhaps there is some other necessary signal that is released by astrocytes along with GABA to influence microglial anti-inflammatory behavior.

Researchers have linked neuroinflammation to other neurodegenerative diseases, so the applicability of this mechanism of action could be widespread.

New Research Into The Link Between Metals and Neurodegenerative Diseases

Peres, T. V., Parmalee, N. L., Martinez-Finley, E. J., and Aschner, M. (2016). Untangling the Manganese-α-Synuclein Web. Front. Neurosci. Frontiers in Neuroscience 10. doi:10.3389/fnins.2016.00364.

In this article the authors review manganese’s interaction with alpha-synuclein protein as a possible cause of dopaminergic related neurodegenerative diseases such as Parkinson’s. The hallmark of Parkinson’s is alpha-synuclein aggregation in which groups of the protein forms into tangles that cause cell death.  They note that disease of excess manganese (manganism),  and Parkinson’s both involve the dopaminergic systems, but in different areas of the brain.

After reviewing several studies, the authors suggest that manganese is likely only a contributing factor to alpha-synuclein aggregation. It is suggested that it interacts with other metals in the brain in a complex web to cause disease.  The observation of this interaction, in various experiments cited, leads the authors to ultimately conclude that alpha-synuclein may be neuroprotective by helping to scavenge excess metals in the brain, but the protein ultimately gets overwhelmed and begins to form tangles as levels of metals rise and are unable to be cleared from the brain.

The metals that cause alpha-synuclein to tangle up and cause disease are aluminum, copper, cadmium, iron, manganese, and zinc (Paik et al., 1999). Cadmium is a well known toxic metal and should be avoided. Aluminum is present in a wide variety of products and even in food additives and serves no nutritional purpose. Thus, limiting exposure to aluminum might be a practical way to protect against neurodegenerative disease.