I have discussed both neurogenesis and curcumin in my treatise and in numerous blog entries but have never examined their relationship. This blog entry is about the actions of curcumin in promoting neurogenesis in the hippocampus and highly-likely mental-health implications of taking curcumin supplements. Finally, I touch on something else that is new – on how curcumin might possibly contribute to longevity by inhibiting mTOR pathway signaling.
Background on neurogenesis and curcumin
Prior to 1999, scientific dogma said that the adult supply of brain cells could not be replenished. Once brain cells died they were irrevocably lost. Then in 1999 researchers at Princeton University reported in the Oct. 15 issue of Science that in adultprimates “the formation of new neurons or nerve cells — neurogenesis — takes place in several regions of the cerebral cortex that are crucial for cognitive and perceptual functions(ref).”
An introductory discussion of neurogenesis can be found in my treatise in the section on the Neurological degeneration theory of aging. “Increasing research evidence suggests that maintaining a sufficient and consistent rate of neurogenesis in the brain, particularly in the hippocampus, is important for the maintenance of cognitive health. Insufficient or irregular neurogenesis is thought to be a causative factor in bipolar disease and other mood disorders. Neurogenesis takes place throughout the life of a mammal in two major brain structures: the dentate gyrus of the hippocampus and the subventricular zone of the forebrain. In these regions neural progenitor cells continuously divide and give birth to new neurons and glial cells. In the mammalian brain neural progenitor cells are multipotent. They can differentiate into neurons, astrocytes or oligodendrocytes, though the factors that determine differentiation are poorly understood. The rate of neurogenesis tends to decline with advancing age in old mammals, as well as the does the number of functional neurons.”
Also, see the discussion of neurogenesis with respect to lifestyle and diet in the Neurological Degeneration Firewall section and in the blog posts Mental exercise and dementia in the news again and Brain fitness, Google and comprehending longevity. Finally, a blog post relevant to the actions of curcumin discussed below is BDNF gene – personality, mental balance, dementia, aging and epigenomic imprinting.
If you do a search in this blog or in my treatise for curcumin, you will see that it long has been one of the favorite substances in my anti-aging firewall regimen for good reasons: it is anti-inflammatory, it is known to combat numerous cancers, it inhibits the expression of NF-kappaB, it can help regulate P53, P21, CASP9 and other genes which control apoptosis, inhibition of cell growth and cell cycle arrest so as to maintain a line of cells in a healthy state, it is a COX-2 enzyme inhibitor, it protects against bone loss, it chelates heavy metals – and the list goes on and on. The actions of this substance are complex. For example, it appears that curcumin acts to control the proliferation of neurogliaoma cells by modulating gene expression related to at least four different pathways: oxidative stress, cell cycle control, and DNA transcription and metabolism(ref).
Quoting from the 2007 publication Curcumin: the Indian solid gold “Curcumin exhibits activities similar to recently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE, and ENBREL), a vascular endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth factor receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker (e.g., HERCEPTIN). Considering the recent scientific bandwagon that multitargeted therapy is better than monotargeted therapy for most diseases, curcumin can be considered an ideal “Spice for Life”.”
Neuroprotective effects of curcumin
The 2005 publication Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition relates to the effects of but not the process of neurogenesis in rat’s brains. “Here, we evaluated the capacity of the powerful antioxidant curry spice curcumin ingested in the diet to counteract the oxidative damage encountered in the injured brain. In addition, we have examined the possibility that dietary curcumin may favor the injured brain by interacting with molecular mechanisms that maintain synaptic plasticity and cognition. The analysis was focused on the BDNF system based on its action on synaptic plasticity and cognition by modulating synapsin I and CREB. Rats were exposed to a regular diet or a diet high in saturated fat, with or without 500 ppm curcumin for 4 weeks (n = 8/group), before a mild fluid percussion injury (FPI) was performed. The high-fat diet has been shown to exacerbate the effects of TBI on synaptic plasticity and cognitive function. Supplementation of curcumin in the diet dramatically reduced oxidative damage and normalized levels of BDNF, synapsin I, and CREB that had been altered after TBI. Furthermore, curcumin supplementation counteracted the cognitive impairment caused by TBI. These results are in agreement with previous evidence, showing that oxidative stress can affect the injured brain by acting through the BDNF system to affect synaptic plasticity and cognition.”
The 2007 publication NEUROPROTECTIVE EFFECTS OF CURCUMIN elaborates further. “Neurodegenerative diseases result in the loss of functional neurons and synapses. Although future stem cell therapies offer some hope, current treatments for most of these diseases are less than adequate and our best hope is to prevent these devastating diseases. Neuroprotective approaches work best prior to the initiation of damage, suggesting that some safe and effective prophylaxis would be highly desirable. Curcumin has an outstanding safety profile and a number of pleiotropic actions with potential for neuroprotective efficacy, including anti-inflammatory, antioxidant, and anti-protein-aggregate activities. These can be achieved at sub-micromolar levels. Curcumin’s dose–response curves are strongly dose dependent and often biphasic so that in vitro data need to be cautiously interpreted; many effects might not be achievable in target tissues in vivo with oral dosing. However, despite concerns about poor oral bioavailability, curcumin has at least 10 known neuroprotective actions and many of these might be realized in vivo. Indeed, accumulating cell culture and animal model data show that dietary curcumin is a strong candidate for use in the prevention or treatment of major disabling age-related neurodegenerative diseases like Alzheimer’s, Parkinson’s, and stroke.” The 2009 publication Neuroprotective effects of curcumin (with the same title but by different authors) carries the same message forward.
The 2009 publication Protective effect of curcumin against intracerebral streptozotocin induced impairment in memory and cerebral blood flow relates: “AIMS: The aim of the present study is to investigate the effect of curcumin on cerebral blood flow (CBF), memory impairment, oxidative stress and cholinergic dysfunction in intracerebral (IC) streptozotocin (STZ) induced memory impairment in mice. MAIN METHODS: Memory impairment was induced by STZ (0.5mg/kg, IC) administered twice with an interval of 48h in mice. Memory function was assessed by Morris water maze and passive avoidance test. CBF was measured by Laser Doppler Flowmetry (LDF). To study the preventive effect, curcumin (10, 20 and 50mg/kg, PO) was administered for 21days starting from the first dose of STZ. In another set of experiment, curcumin was administered for 7days from 19th day after confirming STZ induced dementia to observe its therapeutic effect. Biochemical parameters of oxidative stress and cholinergic function were estimated in brain on day 21. KEY FINDINGS: The major finding of this study is that STZ (IC) caused a significant reduction in CBF along with memory impairment, cholinergic dysfunction and enhanced oxidative stress. Curcumin dose dependently improved CBF in STZ treated mice together with amelioration of memory impairment both in preventive and therapeutic manner. SIGNIFICANCE: The present study clearly demonstrates the beneficial effects of curcumin, the dietary staple of India, on CBF, memory and oxidative stress which can be exploited for dementia associated with age related vascular and neurodegenerative disorders.”
Neurogenesis and curcumin
The researchers back in 1999 used a chemical BrdU as a marker of neurogenesis. “When cells are exposed to BrdU during cell division, the chemical becomes incorporated into the DNA of newly formed cells. The researchers injected BrdU into rhesus monkeys, whose brain structure is fundamentally similar to that of humans. Then, at intervals ranging from two hours to seven weeks, they looked for evidence of the chemical in neurons in the cerebral cortex. In all cases, there were neurons with BrdU in their DNA, which showed that those cells had to have been formed after the BrdU injection(ref).” Similarly BrdU measurements have been used to establish that chronic intake of curcumin promotes neurogenesis in the hippocampus of rat’s brains.
The 2007 research report Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats reports “The aim of this study was to investigate the effects of curcumin on hippocampal neurogenesis in chronically stressed rats. We used an unpredictable chronic stress paradigm (20 days) to determine whether chronic curcumin treatment with the effective doses for behavioral responses (5, 10 and 20 mg/kg, p.o.), could alleviate or reverse the effects of stress on adult hippocampal neurogenesis. Our results suggested that curcumin administration (10 and 20 mg/kg, p.o.) increased hippocampal neurogenesis in chronically stressed rats, similar to classic antidepressant imipramine treatment (10 mg/kg, i.p.). Our results further demonstrated that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. In addition, curcumin significantly prevented the stress-induced decrease in 5-HT1A mRNA and BDNF protein levels in the hippocampal subfields, two molecules involved in hippocampal neurogenesis. These results raise the possibility that increased cell proliferation and neuronal populations may be a mechanism by which curcumin treatment overcomes the stress-induced behavioral abnormalities and hippocampal neuronal damage. Moreover, curcumin treatment, via up-regulation of 5-HT1A receptors and BDNF, may reverse or protect hippocampal neurons from further damage in response to chronic stress, which may underlie the therapeutic actions of curcumin.”
One of the authors of this paper is William Ogle who made a presentation on curcumin and neurogenesis at the Ellison Medical Foundation’s Colloquium on the Biology of Aging at Woods Hole which I attended the week before last. His slides indicate:
· Triple labeling indicated that the BrdU-positive cells observed after curcumin administration to stressed rats indeed matured into neurons.
· “Neurogenesis in the adult hippocampus is regulated by chronic stress. Curcumin regulated the stress-induced decrease in progenitor cell differentiation, indicating that it can increase hippocampal neurogenesis in stressed rats.”
· “Curcumin significantly prevented the stress-induced decrease in 5HT1A mRNA and bdnf protein levels in the hippocampus, two molecules implicated in neurogenesis.”
· The degree of improvement of water-maze learning curves of restraint-stressed rats fed curcumin appears to be dose-dependent. Trials were conducted after stressed animals were fed curcumin for 21 days. Dose-dependent performance improvements were also observed in the latency time required to reach the maze platform and the number of platform crossings. Best results were obtained at a dose of 20mg/kilogram.
· Similarly, the corticosterol levels in stressed rats was reduced by curcumin administration, also in a dose-dependent manner. (Corticosterol is the steroid hormone hydrocortisone which is released in response to stress. It suppresses the immune system and its frequent activation is thought to be life-shortening.) At the highest level of curcumin administration, the corticosterol level was reduced by more than half.
· Curcumin also has an effect on reducing corticosterol-induced death in hippocampal neurons, although dose-dependency is not so striking.
· Curcumin also has a striking dose-dependent effect in reducing CaMKII and pCaMKII expression in corticosterol-treated hippocampal neurons. The same can be said for reducing NMDA-R2B mRNA expression.
· Curcumin-driven neurogenesis in can be seen visibly in representative Golgi-impregnated pyramidal cells for rats from each of the groups taken from the hippocampal CA3 region.· “Curcumin reduces impaired spatial memory under conditions of chronic stress.”
· “Curcumin prevents dendritic hippocampal remodeling under conditions of chronic stress.”
· “Curcumin blocks corticosterone-induced toxicity in primary hippocampal neurons.”
· “Corticosterone-induced phosphorylation of CaMKII is blocked by curcumin in primary hippocampal neurons.”
· “ Curcumin prevents corticosterone-induced increase in NMDA-R mRNA expression in primary hippocampal regions.
Curcumin’s effect on stress are mediated in part by the 5-HT1 and 5-HT2 receptors as discussed in the 2008 paper The antidepressant effects of curcumin in the forced swimming test involve 5-HT1 and 5-HT2 receptors and the 210 paper Differential involvement of 5-HT(1A) and 5-HT(1B/1D) receptors in human interferon-alpha-induced immobility in the mouse forced swimming test.
Curcumin – an inhibitor of mTOR signaling?
Finally, in his presentation at Woods Hole, Ogle speculated that curcumin could possibly act as a mimetic of rapamycin and thus inhibit expression of mTOR. The speculation is based on the molecular structure similarity of the two substances as well as on the health-producing effects of curcumin. Inhibition of mTOR signaling is one of the very few approaches known to provide significant life extension. See the blog entries Longevity genes, mTOR and lifespan, Viva mTOR! Caveat mTOR! and More mTOR links to aging theories.
Considerable weight is given to the speculation by the research reported in the 2010 publication Curcumin Disrupts the Mammalian Target of Rapamycin-Raptor Complex. “Recently, we have shown that curcumin inhibits phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), two downstream effector molecules of the mammalian target of rapamycin complex 1 (mTORC1) in numerous cancer cell lines. This study was designed to elucidate the underlying mechanism. We observed that curcumin inhibited mTORC1 signaling not by inhibition of the upstream kinases, such as insulin-like growth factor 1 receptor (IGF-IR) and phosphoinositide-dependent kinase 1 (PDK1). Further, we found that curcumin inhibited mTORC1 signaling independently of protein phosphatase 2A (PP2A) or AMP-activated protein kinase AMPK-tuberous sclerosis complex (TSC). This is evidenced by the findings that curcumin was able to inhibit phosphorylation of S6K1 and 4E-BP1 in the cells pretreated with PP2A inhibitor (okadaic acid) or AMPK inhibitor (compound C), or in the cells expressing dominant-negative (dn) PP2A, shRNA to PP2A-A subunit, or dn-AMPKÎ±. Curcumin did not alter the TSC1/2 interaction. Knockout of TSC2 did not affect curcumin inhibition of mTOR signaling. Finally, we identified that curcumin was able to dissociate raptor from mTOR, leading to inhibition of mTORC1 activity. Therefore, our data indicate that curcumin may represent a new class of mTOR inhibitor.” This research is based on working with cancer cells but the conclusions are likely to apply to normal cells as well.
I would certainly like it if curcumin is indeed an mTOR inhibitor in normal cells and therefore a major contributor to my longevity. In any event, the research reported here says it is highly likely that curcumin contributes to neurogenesis and maintenance of mental acuity in older people like me. Curcumin remains a central component of my anti-aging firewalls combined supplement regimen.