I attended the Transhuman Visions conference a few years ago, and I’ll be at RAADFest at the end of this week. The most popular topic 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 naturally occurring 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 researchers fed mice 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 that researchers 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 the 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.

Several studies investigated resveratrol’s apparent health-promoting activities. 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]. Researchers initially thought the mechanism of action was via direct activation of SIRT1 [6]. Later researchers discovered that resveratrol did not directly activate SIRT1 but worked through an indirect mechanism [7]. This development led researchers to an indirect activator of SIRT1 known as AMPK, which resveratrol activated. Researchers theorized resveratrol’s neuroprotective effect to be due to its activation of AMPK in neurons [8]. This finding led researchers to ePAC1, an activator of AMPK. cAMP activates ePAC1, and PDE4 inhibition increases cAMP. 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 researchers uncovered PDE4 inhibition 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 help treat age-related diseases [11].

Given 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 researchers have shown luteolin can activate AMPK [14] and is a slightly more potent PDE4 inhibitor than resveratrol [15] [16].

The nootropic concept is that a drug or supplement can improve cognition and benefit 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