By Vince Giuliano

In past blog entries I have focused on research related to a few important plant-derive phyto-substances including resveratrol(ref)(ref),curcumin (ref)(ref), folic acid, valproic acid, caffeic acid, rosmarinic acid, and some of the the phyto-ingredients in olive oil, walnuts, chocolate, hot peppers, and blueberries. But what about good-old-fashioned ginger? It turns out a lot can be said about it.

When I was a child I loved the pungent taste of candied ginger and I would think to myself “This stuff is so strong and exotic that it has to be a powerful good-for-me medicine.” Little did I know! Although long-known as a folk remedy, there was no scientific research evidence for that proposition back then. Now the National Library of Medicine database www.pubmed.org lists 1,369 research citations relating to ginger. Further, the research focus on ginger as well as other phyto substances appears if anything to be intensifying in recent years. Ginger as will see is an antioxidant, a COX-2 inhibitor of inflammation, an inhibitor of inflammatory cytokines, an inhibitor of NF-kappaB, an activator of Nrf2, a modulator of macrophage functions, a cancer chemo preventative, a possible treatment for diarrhea, Alzheimer’s disease pathology and anxiety, can reverse forms of asthma and can help overcome bacterial resistance to an antibiotic.

Ginger “has been traditionally used in Ayurvedic, Chinese and Tibb-Unani herbal medicines for the treatment of various illnesses that involve inflammation and which are caused by oxidative stress(ref).” “Ginger is the rhizome of the plant Zingiber officinale, consumed as a delicacy, medicine, or spice. It lends its name to its genus and family (Zingiberaceae). Other notable members of this plant family are turmeric, cardamom, and galangal(ref).” It is not surprising, therefore, that ginger exerts many of the same biological effects as does curcumin. Curcumin is one of the many ingredients found in ginger although in relatively small amounts. Commercial curcumin is usually derived from turmeric

Some of the most important of these biological effects are covered in the blog entries Neurogenesis, curcumin and longevity and Curcumin, cancer and longevity. The research cited here shows how both ginger and its curcumin component tend to act through the same molecular pathways in organisms.

Image from Kohler’s Medicinal Plants.

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Ginger is a complex substance consisting of more than 60 compounds. “The characteristic odor and flavor of ginger is caused by a mixture of zingerone, shogaols and gingerols, volatile oils that compose one to three percent of the weight of fresh ginger. In laboratory animals, the gingerrols increase the motility of the gastrointestinal tract and have analgesic, sedative, antipyretic and antibacterial properties.^[4] Ginger oil has been shown to prevent skin cancer in mice^[5] and a study at the University of Michigan demonstrated that gingerols can kill ovarian cancer cells.^[6][7][8] [6]-gingerol (1-[4′-hydroxy-3′-methoxyphenyl]-5-hydroxy-3-decanone) is the major pungent principle of ginger. The chemopreventive potentials of [6]-gingerol present a promising future alternative to expensive and toxic therapeutic agents.^[9] — Ginger contains up to three percent of a fragrant essential oil whose main constituents are sesquiterpenoids, with (-)-zingiberene as the main component. Smaller amounts of other sesquiterpenoids (β-sesquiphellandrene, bisabolene and farnesene) and a small monoterpenoid fraction (β-phelladrene, cineol, and citral) have also been identified. — The pungent taste of ginger is due to nonvolatile phenylpropanoid-derived compounds, particularly gingerols and shogaols, which form from gingerols when ginger is dried or cooked. Zingerone is also produced from gingerols during this process; this compound is less pungent and has a spicy-sweet aroma.^[10] ” (ref)

Ginger antioxidant properties

That ginger has antioxidant properties has been known for some time The 2004 publication Antioxidant properties of gingerol related compounds from ginger points out that ginger contains over 50 antioxidant compounds. “Ginger (Zingiber officinale Roscoe) shows an antioxidant activity, and we have been engaging to determine the structures of more than 50 antioxidants isolated from the rhizomes of ginger. The isolated antioxidants are divided into two groups; gingerol related compounds and diarylheptanoids. In this study, structure-activity relationship of gingerol related compounds was evaluated.”

Ginger mechanisms for control of inflammation

The 2011 publication Cyclooxygenase-2 inhibitors in ginger (Zingiber officinale) reports “Ginger roots have been used to treat inflammation and have been reported to inhibit cyclooxygenase (COX). Ultrafiltration liquid chromatography mass spectrometry was used to screen a chloroform partition of a methanol extract of ginger roots for COX-2 ligands, and 10-gingerol, 12-gingerol, 8-shogaol, 10-shogaol, 6-gingerdione, 8-gingerdione, 10-gingerdione, 6-dehydro-10-gingerol, 6-paradol, and 8-paradol bound to the enzyme active site. Purified 10-gingerol, 8-shogaol and 10-shogaol inhibited COX-2 with IC(50) values of 32 μM, 17.5 μM and 7.5 μM, respectively. No inhibition of COX-1 was detected. Therefore, 10-gingerol, 8-shogaol and 10-shogaol inhibit COX-2 but not COX-1, which can explain, in part, the anti-inflammatory properties of ginger.”

Another mechanism used by ginger compounds to inhibit inflammation is attenuation of NF-kappaB-mediated iNOS gene expression. The 2006 publication Gingerol metabolite and a synthetic analogue Capsarol inhibit macrophage NF-kappaB-mediated iNOS gene expression and enzyme activity relates “–Inducible nitric oxide synthase (iNOS), a proinflammatory enzyme responsible for the generation of nitric oxide (NO), has been implicated in the pathogenesis of inflammatory diseases. Gingerols, the main pungent principles of ginger, have anti-inflammatory properties in vitro. In this study we examine the inhibitory effect of a stable [6]-gingerol metabolite, RAC-[6]-dihydroparadol ([6]-DHP) and a closely related gingerol analogue, RAC-2-hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecan-3-one [a capsaicin/gingerol (Capsarol) analogue referred to as ZTX42] on NO production, inducible nitric oxide synthase (iNOS) activity and protein expression levels in a murine macrophage cell line –. — Although both compounds partially inhibited the catalytic activity of iNOS, their inhibitory effect was predominantly due to attenuation of iNOS protein production. This occurred at the transcriptional level, since the gingerol compounds decreased LPS-induced IkappaB-alpha degradation, prevented nuclear translocation of NF-kappaB p65 and reduced NF-kappaB activity in a concentration-dependent manner. Taken together, these results show that ZTX42 and [6]-DHP suppress NO production in murine macrophages by partially inhibiting iNOS enzymatic activity and reducing iNOS protein production, via attenuation of NF-kappaB-mediated iNOS gene expression, providing a rationale for the anti-inflammatory activity reported for this class of compounds.”

Ginger endrocrine and anti-inflammatory functions

The 2011 publication Physiological and therapeutical roles of ginger and turmeric on endocrine functions relates “The natural product ginger (Zingiber officinale) has active constituents gingerol, Shogaol and Zerumbone, while turmeric (Curcuma longa) contains three active major curcuminoids, namely, curcumin, demethoxycurcumin, and bisdemethoxycurcumin. They have the same scientific classification and are reported to have anti-inflammatory and many therapeutic effects. This article reviews the physiological and therapeutic effects of ginger and turmeric on some endocrine gland functions, and signal pathways involved to mediate their actions. With some systems and adipose tissue, ginger and turmeric exert their actions through some/all of the following signals or molecular mechanisms: (1) through reduction of high levels of some hormones (as: T4, leptin) or interaction with hormone receptors; (2) by inhibition of cytokines/adipokine expression; (3) acting as a potent inhibitor of reactive oxygen species (ROS)-generating enzymes, which play an essential role between inflammation and progression of diseases; (4) mediation of their effects through the inhibition of signaling transcription factors; and/or (5) decrease the proliferative potent by down-regulation of antiapoptotic genes, which may suppress tumor promotion by blocking signal transduction pathways in the target cells. These multiple mechanisms of protection against inflammation and oxidative damage make ginger and curcumin particularly promising natural agents in fighting the ravages of aging and degenerative diseases, and need to be paid more attention by studies.”

The 2010 publication Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol relates “Although gingerols and shogaols are the major bioactive compounds present in Zingiber officinale, their molecular mechanisms of actions and the relationship between their structural features and the activity have not been well studied. — The aim of the present study was to examine and compare the antioxidant and anti-inflammatory activities of gingerols and their natural analogues to determine their structure-activity relationship and molecular mechanisms.” The in-vitro antioxidant assay produced the conclusions “Shogaol has exhibited the most potent antioxidant and anti-inflammatory properties which can be attributed to the presence of alpha,beta-unsaturated ketone moiety. The carbon chain length has also played a significant role in making 10-gingerol as the most potent among all the gingerols. This study justifies the use of dry ginger in traditional systems of medicine.”

Ginger and phagocytosis

Ginger can enhance the functional capability of phagocytes “to protect the body by ingesting (phagocytosing) harmful foreign particles, bacteria, and dead or dying cells.” (ref). The 2009 publication Modulation of macrophage functions by compounds isolated from Zingiber officinale reports on the most bioactive ginger compounds in this regard: “Bioactivity-guided fractionation of Zingiber Officinale (zingiberaceae) led us to isolate 14 compounds, -gingerol ( 1), -gingerol ( 2), -gingerol ( 3), -gingerol ( 4), -paradol ( 5), -shogaol ( 6), -shogaol ( 7), 1-dehydro- -gingerdione ( 8), -gingerdione ( 9), hexahydrocurcumin ( 10), tetrahydrocurcumin ( 11), gingerenone A ( 12), 1,7-bis-(4′ hydroxyl-3′ methoxyphenyl)-5-methoxyhepthan-3-one ( 13), and methoxy- -gingerol ( 14). Using the RAW 264.7 cell line, the inhibitory effects on nitric oxide production induced by lipopolysaccharide and the stimulatory effects on phagocytosis of these compounds were evaluated. Compounds 7, 8, and 9 significantly decreased lipopolysaccharide-induced nitric oxide production, and compounds 7 and 8 significantly reduced inducible nitric oxide synthase expression. Among them, compound 8 also showed significant stimulatory effects on phagocytosis.”

Cancer chemoprevention

In my blog post Cancer, epigenetics and dietary substances I introduced the post by stating “We have long known from large population studies that regular consumption of certain dietary substances and supplements like green tea, olive oil, blueberries, oregano, ginger and hot chili peppers can negatively impact on incidences of cancer. We also know from multiple studies that certain plant-based polyphenol substances like rosmarinic acid, curcumin, lycopene, caffeic acid, resveratrol and gingerol inhibit the development of certain cancers. Indeed this research has been the basis for my suggested lifestyle and dietary supplement anti-aging regimens.” The same seems to be true for ginger as related in the 2007 publication Cancer preventive properties of ginger: a brief review.

Ginger induces apoptosis in various lines of cancer cells. For example, the 2010 document Induction of apoptosis by [8]-shogaol via reactive oxygen species generation, glutathione depletion, and caspase activation in human leukemia cells reports “This study examined the growth inhibitory effects of [8]-shogaol, one of the pungent phenolic compounds in ginger, on human leukemia HL-60 cells. It demonstrated that [8]-shogaol was able to induce apoptosis in a time- and concentration-dependent manner. Treatment with [8]-shogaol caused a rapid loss of mitochondrial transmembrane potential, stimulation of reactive oxygen species (ROS) production, release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 and procaspase-3 processing. Taken together, these results suggest for the first time that ROS production and depletion of glutathione that contributed to [8]-shogaol-induced apoptosis in HL-60 cells.”

Ginger compounds can promote P53 apoptosis of cancer cells. The 2010 publication Induction of apoptosis by [6]-gingerol associated with the modulation of p53 and involvement of mitochondrial signaling pathway in B[a]P-induced mouse skin tumorigenesis reports “Topical treatment of [6]-gingerol (2.5 muM/animal) was given to the animals 30 min prior and post to B[a]P (5 mug/animal) for 32 weeks. At the end of the study period, the skin tumors/tissues were dissected out and examined histopathologically. Flow cytometry was employed for cell cycle analysis. Further immunohistochemical localization of p53 and regulation of related apoptogenic proteins were determined by Western blotting. — Chemopreventive properties of [6]-gingerol were reflected by delay in onset of tumorigenesis, reduced cumulative number of tumors, and reduction in tumor volume. Cell cycle analysis revealed that the appearance of sub-G1 peak was significantly elevated in [6]-gingerol treated animals with post treatment showing higher efficacy in preventing tumorigenesis induced by B[a]P. Moreover, elevated apoptotic propensity was observed in tumor tissues than the corresponding non-tumor tissues. Western blot analysis also showed the same pattern of chemoprevention with [6]-gingerol treatment increasing the B[a]P suppressed p53 levels, also evident by immunohistochemistry, and Bax while decreasing the expression of Bcl-2 and Survivin. Further, [6]-gingerol treatment resulted in release of Cytochrome c, Caspases activation, increase in apoptotic protease-activating factor-1 (Apaf-1) as mechanism of apoptosis induction. — On the basis of the results we conclude that [6]-gingerol possesses apoptotic potential in mouse skin tumors as mechanism of chemoprevention hence deserves further investigation.”

Ginger compounds limit cancer-related angiogenesis. The 2005 publication [6]-Gingerol, a pungent ingredient of ginger, inhibits angiogenesis in vitro and in vivo relates “[6]-Gingerol, a pungent ingredient of ginger (Zingiber officinale Roscoe, Zingiberaceae), has anti-bacterial, anti-inflammatory, and anti-tumor-promoting activities. Here, we describe its novel anti-angiogenic activity in vitro and in vivo. In vitro, [6]-gingerol inhibited both the VEGF- and bFGF-induced proliferation of human endothelial cells and caused cell cycle arrest in the G1 phase. It also blocked capillary-like tube formation by endothelial cells in response to VEGF, and strongly inhibited sprouting of endothelial cells in the rat aorta and formation of new blood vessel in the mouse cornea in response to VEGF. Moreover, i.p. administration, without reaching tumor cytotoxic blood levels, to mice receiving i.v. injection of B16F10 melanoma cells, reduced the number of lung metastasis, with preservation of apparently healthy behavior. Taken together, these results demonstrate that [6]-gingerol inhibits angiogenesis and may be useful in the treatment of tumors and other angiogenesis-dependent diseases.”

Another of the impacts of ginger on certain cancer cells appears to be inhibition of proliferation-related genes through inhibiting expression of NF-kappaB and COX-2 induction.  The 2004 publication Inhibitory effects of [6]-gingerol on PMA-induced COX-2 expression and activation of NF-kappaB and p38 MAPK in mouse skin relates “. Previous studies have demonstrated that [6]-gingerol inhibits mouse skin tumor promotion and anchorage-independent growth of cultured mouse epidermal cells stimulated with epidermal growth factor. Cyclooxygenase-2 (COX-2), a key enzyme in the prostaglandin biosynthesis, has been recognized as a molecular target for many anti-inflammatory as well as chemopreventive agents. Topical application of [6]-gingerol inhibited phorbol 12-myristate 13-acetate -induced COX-2 expression. One of the essential transcription factors responsible for COX-2 induction is NF-kappaB. [6]-Gingerol suppressed NF-kappaB DNA binding activity in mouse skin. In addition, [6]-gingerol inhibited the phoshorylation of p38 mitogen-activated protein kinase which may account for its inactivation of NF-kappaB and suppression of COX-2 expression.”

These same factors are also discussed in the 2007 publication Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells. “Ginger (Zingiber officinale Rosc) is a natural dietary component with antioxidant and anticarcinogenic properties. The ginger component [6]-gingerol has been shown to exert anti-inflammatory effects through mediation of NF-kappaB. NF-kappaB can be constitutively activated in epithelial ovarian cancer cells and may contribute towards increased transcription and translation of angiogenic factors. In the present study, we investigated the effect of ginger on tumor cell growth and modulation of angiogenic factors in ovarian cancer cells in vitro. The effect of ginger and the major ginger components on cell growth was determined in a panel of epithelial ovarian cancer cell lines. Activation of NF-kappaB and and production of VEGF and IL-8 was determined in the presence or absence of ginger. — Ginger treatment of cultured ovarian cancer cells induced profound growth inhibition in all cell lines tested. We found that in vitro, 6-shogaol is the most active of the individual ginger components tested. Ginger treatment resulted in inhibition of NF-kB activation as well as diminished secretion of VEGF and IL-8. — Ginger inhibits growth and modulates secretion of angiogenic factors in ovarian cancer cells. The use of dietary agents such as ginger may have potential in the treatment and prevention of ovarian cancer.”

Also see the 2009 publication Ginger’s (Zingiber officinale Roscoe) inhibition of rat colonic adenocarcinoma cells proliferation and angiogenesis in vitro and the 2008 publication 6-Shogaol suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages.

.Another mechanism of action of ginger on cancer cells onvolves TRAIL. TRAIL stand for tumor necrosis factor–related apoptosis-inducing ligand. TRAIL is also called APO-2L and consists of 281 amino acids. Regarding TRAIL as an approach to cancer therapy see the blog entry On the TRAIL of a selective cancer treatment. The 2007 publication Ginger ingredients reduce viability of gastric cancer cells via distinct mechanisms reports “We found that 6-gingerol, a phenolic alkanone isolated from ginger, enhanced the TRAIL-induced viability reduction of gastric cancer cells while 6-gingerol alone affected viability only slightly. 6-Gingerol facilitated TRAIL-induced apoptosis by increasing TRAIL-induced caspase-3/7 activation. 6-Gingerol was shown to down-regulate the expression of cIAP1, which suppresses caspase-3/7 activity, by inhibiting TRAIL-induced NF-kappaB activation. As 6-shogaol has a chemical structure similar to 6-gingerol, we also assessed the effect of 6-shogaol on the viability of gastric cancer cells. Unlike 6-gingerol, 6-shogaol alone reduced the viability of gastric cancer cells. 6-Shogaol was shown to damage microtubules and induce mitotic arrest. These findings indicate for the first time that in gastric cancer cells, 6-gingerol enhances TRAIL-induced viability reduction by inhibiting TRAIL-induced NF-kappaB activation while 6-shogaol alone reduces viability by damaging microtubules.”

The anti-cancer effects of ginger involving TRAIL seem to be similar to those of many other plant phytochemicals. In an my blog entry on TRAIL I wrote “Certain of the supplements in the Susceptibility to Cancer firewall, particularly curcumin(ref), resveratrol(ref) and green tea, owe at least some of their anti-cancer effects to the operation of TRAIL. In the case of prostate and other cancers, curcumin inhibits the activation of NF-kappaB which makes them more sensitive to apoptosis by TRAIL(ref,ref,ref). Resveratrol appears to have the same effect in certain tumors(ref)(ref). The same appears to be true for EGCG, the major active constituent of green tea(ref). I speculate that other plant-derived polyphenols in the anti-cancer firewall might have similar effects, enhancing TRAIL-mediated death receptor activation in cancer cells. Possibly, most of the 39 inhibitors of NF-kappaB in the firewall might work to empower TRAIL and fight cancers in the same way.”

Ginger has also been shown to inhibit the expression of telomerase in certain cancer cells. The December 2010 publication Ginger extract inhibits human telomerase reverse transcriptase and c-Myc expression in A549 lung cancer cells reports “. Here we show that the ethyl acetate fraction of ginger extract can inhibit the expression of the two prominent molecular targets of cancer, the human telomerase reverse transcriptase (hTERT) and c-Myc, in A549 lung cancer cells in a time- and concentration-dependent manner. The treated cells exhibited diminished telomerase activity because of reduced protein production rather than direct inhibition of telomerase. The reduction of hTERT expression coincided with the reduction of c-Myc expression, which is one of the hTERT transcription factors; thus, the reduction in hTERT expression might be due in part to the decrease of c-Myc. As both telomerase inhibition and Myc inhibition are cancer-specific targets for cancer therapy, ginger extract might prove to be beneficial as a complementary agent in cancer prevention and maintenance therapy.”

A 2008 publication relates to cytotoxicity of ginger compounds to cancer cells: Cytotoxic components from the dried rhizomes of Zingiber officinale Roscoe. “Five compounds were isolated from the chloroform-soluble fraction of the methanolic extract of the dried rhizomes of Zingiber officinale (Zingiberaceae) through repeated column chromatography. Their chemical structures were elucidated as 4-, 6-, 8-, and 10-gingerols, and 6-shogaol using spectroscopic analysis. Among the five isolated compounds, 6-shogaol exhibited the most potent cytotoxicity against human A549, SK-OV-3, SK-MEL-2, and HCT15 tumor cells. 6-shogaol inhibited proliferation of the transgenic mouse ovarian cancer cell lines, C1 (genotype: p53(-/-), c-myc, K-ras) and C2 (genotype: p53(-/-), c-myc, Akt), with ED(50) values of 0.58 microM (C1) and 10.7 microM (C2).”

The relative anti-carcinogenic effectiveness of gingerol and shogaol compounds in ginger is dealt with in the 2009 publication Increased growth inhibitory effects on human cancer cells and anti-inflammatory potency of shogaols from Zingiber officinale relative to gingerols. “Ginger, the rhizome of the plant Zingiber officinale , has received extensive attention because of its antioxidant, anti-inflammatory, and antitumor activities. Most researchers have considered gingerols as the active principles and have paid little attention to shogaols, the dehydration products of corresponding gingerols during storage or thermal processing. In this study, we have purified and identified eight major components, including three major gingerols and corresponding shogaols, from ginger extract and compared their anticarcinogenic and anti-inflammatory activities. Our results showed that shogaols ([6], [8], and [10]) had much stronger growth inhibitory effects than gingerols ([6], [8], and [10]) on H-1299 human lung cancer cells and HCT-116 human colon cancer cells, especially when comparing [6]-shogaol with [6]-gingerol (IC50 of approximately 8 versus approximately 150 microM). In addition, we found that [6]-shogaol had much stronger inhibitory effects on arachidonic acid release and nitric oxide (NO) synthesis than [6]-gingerol.”

You can also see Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol and Mode of action of gingerols and shogaols on 5-HT3 receptors: binding studies, cation uptake by the receptor channel and contraction of isolated guinea-pig ileum.

In my blog entry Nrf2 and cancer chemoprevention by phytochemicals I indicated “A cluster of research reports has appeared during the last few years looking at mechanisms through which substances rich in phytochemicals (e.g. coffee, chocolate, turmeric, olive oil, broccoli, red hot peppers, green tea, garlic, blueberries, rosemary, oregano, sage) are cancer-preventative. While these foods have been studied for many years a new focal point has been moving to center stage – study of what these substances are doing in terms of gene expression as a key to understanding their therapeutic value. — Recent studies have provided strong evidence that many daily-consumed dietary compounds possess cancer-protective properties that might interrupt the carcinogenesis process. These properties include the induction of cellular defense detoxifying and antioxidant enzymes, which can protect against cellular damage caused by environmental carcinogens or endogenously generated reactive oxygen species. These compounds can also affect cell-death signaling pathways, which could prevent the proliferation of tumor cells.” — One master activator of antioxidant and anticancer genes appears to be Nuclear factor-erythroid-2-related factor 2 (Nrf2). The sequence of events involved in phytochemical chemoprevention mediated by Nrf2 is complex and is summarized in the 2008 publication Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. “A wide array of dietary phytochemicals have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and elimination/inactivation of electrophilic carcinogens. Induction of such cytoprotective enzymes by edible phytochemicals largely accounts for their cancer chemopreventive and chemoprotective activities.” For those of you who have a taste for molecular biology, that document goes on to explain “Nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a crucial role in the coordinated induction of those genes encoding many stress-responsive and cytoptotective enzymes and related proteins. These include NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, thioredoxin, etc. In resting cells, Nrf2 is sequestered in the cytoplasm as an inactive complex with the repressor Kelch-like ECH-associated protein 1 (Keap1). The release of Nrf2 from its repressor is most likely to be achieved by alterations in the structure of Keap1. Keap1 contains several reactive cysteine residues that function as sensors of cellular redox changes. Oxidation or covalent modification of some of these critical cysteine thiols would stabilize Nrf2, thereby facilitating nuclear accumulation of Nrf2. After translocation into nucleus, Nrf2 forms a heterodimer with other transcription factors, such as small Maf, which in turn binds to the 5′-upstream CIS-acting regulatory sequence, termed antioxidant response elements (ARE) or electrophile response elements (EpRE), located in the promoter region of genes encoding various antioxidant and phase 2 detoxifying enzymes. Certain dietary chemopreventive agents target Keap1 by oxidizing or chemically modifying one or more of its specific cysteine thiols, thereby stabilizing Nrf2. In addition, phosphorylation of specific serine or threonine residues present in Nrf2 by upstream kinases may also facilitate the nuclear localization of Nrf2. Multiple mechanisms of Nrf2 activation by signals mediated by one or more of the upstream kinases, such as mitogen-activated protein kinases, phosphatidylionositol-3-kinase/Akt, protein kinase C, and casein kinase-2 have recently been proposed.”

Neurological actions of ginger

Ginger fractions bind to a serotonin receptor and reduces levels of anxiety in animals. The 2010 publication Identification of serotonin 5-HT1A receptor partial agonists in ginger reports: “Animal studies suggest that ginger (Zingiber officinale Roscoe) reduces anxiety. In this study, bioactivity-guided fractionation of a ginger extract identified nine compounds that interact with the human serotonin 5-HT(1A) receptor with significant to moderate binding affinities (K(i)=3-20 microM). [(35)S]-GTP gamma S assays indicated that 10-shogaol, 1-dehydro-6-gingerdione, and particularly the whole lipophilic ginger extract (K(i)=11.6 microg/ml) partially activate the 5-HT(1A) receptor (20-60% of maximal activation). In addition, the intestinal absorption of gingerols and shogaols was simulated and their interactions with P-glycoprotein were measured, suggesting a favourable pharmacokinetic profile for the 5-HT(1A) active compounds.”

Relevant to Alzheimer’s disease pathology is the 2011 publication [6]-Gingerol attenuates β-amyloid-induced oxidative cell death via fortifying cellular antioxidant defense system. “β-Amyloid (Aβ) is involved in the formation of senile plaques, the typical neuropathological marker for Alzheimer’s disease (AD) and has been reported to cause apoptosis in neurons via oxidative and/or nitrosative stress. In this study, we have investigated the neuroprotective effect and molecular mechanism of [6]-gingerol, a pungent ingredient of ginger against Αβ(25-35)-induced oxidative and/or nitrosative cell death in SH-SY5Y cells. [6]-Gingerol pretreatment protected against Aβ(25-35)-induced cytotoxicity and apoptotic cell death such as DNA fragmentation, disruption of mitochondrial membrane potential, elevated Bax/Bcl-2 ratio, and activation of caspase-3. To elucidate the neuroprotective mechanism of [6]-gingerol, we have examined Aβ(25-35)-induced oxidative and/or nitrosative stress and cellular antioxidant defense system against them. [6]-Gingerol effectively suppressed Aβ(25-35)-induced intracellular accumulation of reactive oxygen and/or nitrogen species and restored Aβ(25-35)-depleted endogenous antioxidant glutathione levels. Furthermore, [6]-gingerol treatment up-regulated the mRNA and protein expression of antioxidant enzymes such as γ-glutamylcysteine ligase (GCL) and heme oxygenase-1 (HO-1), the rate limiting enzymes in the glutathione biosynthesis and the degradation of heme, respectively. The expression of aforementioned antioxidant enzymes seemed to be mediated by activation of NF-E2-related factor 2 (Nrf2). These results suggest that [6]-gingerol exhibits preventive and/or therapeutic potential for the management of AD via augmentation of antioxidant capacity.” I discussed the roles of Nrf2 above.

Ginger and respiratory diseases

Interesting new findings related to asthma are reported in the April 2011 publication Ginger suppresses phthalate ester-induced airway remodeling. “This study has two novel findings: it is not only the first to demonstrate inflammatory cytokines, which are produced by the bronchial epithelium after exposure to phthalate esters and contribute to airway remodeling by increasing human bronchial smooth muscle cells (BSMC) migration and proliferation, but it is also the first to reveal that ginger reverses phthalate ester-mediated airway remodeling. –. Moreover, [6]-shogaol, [6]-gingerol, [8]-gingerol, and [10]-gingerol, which are major bioactive compounds present in Zingiber officinale , suppress phthalate ester-mediated airway remodeling. This study suggests that ginger is capable of preventing phthalate ester-associated asthma.”

Ginger and gastrointestinal diseases

Ginger compounds may be useful for controlling some intestinal diseases. The 2011 publication Effects of Ginger Constituents on the Gastrointestinal Tract: Role of Cholinergic M3 and Serotonergic 5-HT3 and 5-HT4 Receptors reports “The herbal drug ginger ( ZINGIBER OFFICINALE Roscoe) may be effective for treating nausea, vomiting, and gastric hypomotility.”

The 2011 publication Intraluminal administration of zingerol, a non-pungent analogue of zingerone, inhibits colonic motility in rats reports “Zingerone, a pungent component of ginger, may exert beneficial therapeutic effects on hypermotilityinduced diarrhea because it has the ability to inhibit contractions of colonic smooth muscles. However, the pungency is undesirable for possible therapeutic use. The purpose of this study was to examine effects of zingerol, a non-pungent analogue of zingerone, in rats. — These findings suggest that zingerol can inhibit colonic motility without adverse effects on small intestinal motility and the cardiovascular system. The non-pungent property of zingerol will be useful as an oral or suppository medicine for treating diarrhea and other gastrointestinal disorders.”

Ginger and the immune system

At least one component of ginger is immunosuppressive as pointed out in the 2011 publication Immunosuppressive activity of 8-gingerol on immune responses in mice. “8-gingerol is one of the principal components of ginger, which is widely used in China and elsewhere as a food, spice and herb. It shows immunosuppressive activity on the immune responses to ovalbumin (OVA) in mice. In the present study, we found that 8-gingerol suppressed lipopolysaccharide (LPS) and concanavalin A (ConA)-stimulated splenocyte proliferation in vitro. In vivo, 8-gingerol not only significantly suppressed Con A-, LPS- and OVA-induced splenocyte proliferation (P < 0.05) but also decreased the percentage of CD19+ B cells and CD3+ T cell (P < 0.05) at high doses (50, 100 mg/kg). Moreover, OVA-specific IgG, IgG1 and IgG2b levels in OVA-immunized mice were reduced by 8-gingerol at doses of 50, 100 mg/kg. These results suggest that 8-gingerol could suppress humoral and cellular immune responses in mice. The mechanism might be related to direct inhibition of sensitized T and B lymphocytes.”

Ginger and bacterial resistance to tetracycline

The 2010 publication Zingiber officinale (ginger) compounds have tetracycline-resistance modifying effects against clinical extensively drug-resistant Acinetobacter baumannii reports “Extensively drug-resistant Acinetobacter baumannii (XDRAB) is a growing and serious nosocomial infection worldwide, such that developing new agents against it is critical. The antimicrobial activities of the rhizomes from Zingiber officinale, known as ginger, have not been proven in clinical bacterial isolates with extensive drug-resistance. This study aimed to investigate the effects of four known components of ginger, [6]-dehydrogingerdione, [10]-gingerol, [6]-shogaol and [6]-gingerol, against clinical XDRAB. All these compounds showed antibacterial effects against XDRAB. Combined with tetracycline, they showed good resistance modifying effects to modulate tetracycline resistance.”

Final observations

Ginger is an impressive and far from boring substance when looked at through the lenses of current medical-related research. I expect we will be hearing more and more about curative and life-extending properties of ginger-derived compounds as time proceeds.

However, I have seen little-to-no research so far regarding the effects of ginger as an epigenetic modifier, whether or how ginger affects gene promotion, or regarding possible impacts of ginger compounds on stem cell quiescence or activation. The same is true for most of the other important dietary phyto-substances, resveratrol and curcumin being partial exemptions. I am looking forward to seeing and reporting on such research as it eventually appears.

By Victor

Since its discovery in 1979, p53 has never stopped surprising researchers. For a decade, it was thought to be an oncogene (a gene that causes cancer). In 1989, it was found to have the opposite role of suppressing tumors. (ref) It was originally thought to be a transcriptional activator, until it was discovered to also be a repressor. (ref) It was then discovered that not only did p53 function within the cell nucleus, but also in the cytoplasm, regulating mitochondrial activity. (ref) p53 is known to play a very surprising role in the cancer-protective process of UV skin tanning. (ref) A similar response to UV light is known to have protected our invertebrate ancestors from the potentially harmful effects of radiation one billion years ago, indicating that the function of p53 has been preserved for, at least, one million millenia. (ref) A further surprise came when p53 was found to have an important role in aging and longevity, which will be the focus of this discussion.

A more detailed discussion of p53 in cancer prevention can be found in an earlier blog entry by Dr. Guiliano, Turning p53 On in Cancer Cells.

What exactly is p53?

p53 actually refers to a family of closely related transcription factors consisting of p53, p63, and p73, each of which has various isoforms with distinct effects. (ref) (An isoform is different form, or variant of the same protein which may result from alternative splicing of the same gene.) Although they are referred to as “transcription factors”, due to their ability to interact with the process of genetic transcription, their effects are not limited to nuclear transcription, but also include post translational modifications, and many protein-protein interactions involved in a variety of signaling pathways. All three subfamilies target the same genes; and all three play important roles in cell-cycle regulation, including the hallmark ability to suppress tumorigenesis by inducing cell-cycle arrest. Such arrest may be temporary, allowing for DNA repair (quiesence), or permanent (senescence), or result in cellular death (apoptosis). Knockout mice studies have shown that p63 is especially important for regulation of epithelial tissues, including normal development and repair, while p73 is crucial for normal differentiation and development of neurons. (ref)

Interplay between p53 subfamilies and isoforms.

Various members of the p53 family play distinct, but similar, and complementary roles in suppressing tumorigenesis, and in the regulation of other cellular functions. A great deal of interaction between different p53 subfamilies and their various isoforms is known to take place. The importance of p53 subfamily interaction is exemplified by the fact that, without the presence of p63 and p73, p53 alone is unable to induce apoptosis in DNA-damaged cells. (ref) However, this interaction is not always, complementary. Truncated isoforms, lacking the N-terminal or transactivation domain, are constitutively active, meaning they are always active; for this reason, they are also said to be “unregulated”. Regulated, transactivating isoforms are activated in response to cellular stress signals. (Cellular stress can be the result of nutrient scarcity, aberrant metabolic activity, reactive oxygen species, inflammation, etc.) Truncated isoforms of all three subfamilies are known to antagonize the regulated activity of the complete, transactivaing isoforms. (ref, ref) To distinguish them from their truncated variants, transactivating isoforms are often written with a TA prefix, i.e. TAp53, TAp63, etc. Mutant p53 variants are also known to form mutant complexes with normal isoforms, thereby altering their function or deactivating them. (ref)

Guardians of the genome.

All three subfamilies play complementary roles in maintaining the genomic integrity and viability of germ line cells. For this reason, the p53 family has been collectively referred to as the “guardian of the genome”, while the p63, which is constitutively expressed in female germ cells during meiotic arrest, and is necessary for apoptosis of DNA-damaged oocytes, has been referred to as “the guardian of the female germ line”. See: p63 protects the female germ line , p73 knockout shows genomic instability with infertility –, and A male germ cell tumor-susceptibility-determining locus — .

p53 is also known as the “guardian of the somatic genome”:

“Within the higher vertebrates, p63 and p73 have taken on new functions in development of tissues and organs, whereas p53 has become the guardian of the somatic genome and a tumor suppressor. With the advent of employing large numbers of stem cells and tissue regeneration as a strategy for an organism’s growth, development, and maintenance, there is a greater need for stem cell surveillance to prevent cancers from arising. p53 evolved to fill this role. It is of some interest that p53 has recently been shown to regulate the efficiency of induced pluripotent stem cell production from differentiated cells (13–17) indicating a new possible role for p53 in enforcing the direction of developmental processes in a cell. There is an intimate relationship among p53, stem cell development, and epigenetic regulation of these processes, and it began to evolve in the fishes.” (ref)

The aging connection: Antagonistic Pleiotropy.

Originally proposed in 1957, the basic idea behind the theory of antagonistic pleiotropy is that the forces of natural selection will give preference to genes that promote survival in the earlier stages of life, even if they are detrimental to survival in later life. Clearly, if an organism doesn’t survive the early stages, then genes that promote survival in later life are meaningless. Furthermore, once an organism passes its reproductive stage, the genomic value of continued survival becomes less clear. Some have considered p53 an ideal candidate for such a gene. They reason that there is a tradeoff between youthful health, and longevity. By inducing cell-cycle arrest in suspect cells, p53 protects against cancer and other degenerative diseases, but at the cost of reducing future supplies of viable cells, leading to senescence and premature aging. See: The common biology of cancer and ageing. See also: Stem Cell Supply Chain Breakdown.

What is the role of the p53 family in aging? Examining the evidence.

In 2002 and 2004, two landmark studies demonstrated that mice with increased p53 activity, while extraordinarily resistant to cancer, showed multiple signs of accelerated aging, and died prematurely. See: p53 mutant mice that display early ageing-associated phenotypes, and Modulation of mammalian life span by the short isoform of p53. Overexpression of p53 was thought to result in chronic apoptosis resulting in cancer protection, at the cost of tissue atrophy or dysfunction, leading to premature death. (ref) A more recent 2009 study shows that overexpression of p53 results in depletion of neural stem supplies, directly leading to decline in normal brain function.

Regenerative capacity of neural precursors in the adult mammalian brain is under the control of p53: “We determined that the impaired ability of NSCs to proliferate does indeed limit the supply of newly generated neurons in the adult brain in an age-dependent way. We also determined that brain function (olfaction) and stem and progenitor cell proliferation declined in parallel. We propose that p53 is a central regulator of neurogenesis in the adult mammalian brain. . . Our results suggest that during aging this regulatory mechanism deteriorates, resulting in disruptions in the ability of stem cells to proliferate. As a consequence, neurogenic regions in the adult brain lose the capacity to replace neurons lost through attrition and normal brain function declines.”

Contradictory Evidence.

Not all studies have shown a reduction in longevity associated with increased p53 activity. Mice with an extra copy of the wild-type p53 gene, showed increased p53 activity, and increased cancer resistance, but with no signs of accelerated aging, and a normal lifespan. See: “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. In another model, p53 overexpression was achieved by reducing activity of a known p53 inhibitor, murine double-minute gene 2 (Mdm2). See: Tumor suppression and normal aging in mice with constitutively high p53 activity. Once again, extraordinary cancer resistance was accomplished, with no adverse effects on aging or lifespan. In a third study, “genetically manipulated mice with increased, but otherwise normally regulated, levels of Arf and p53 present strong cancer resistance and have decreased levels of age-associated damage. These observations extend the protective role of Arf/p53 to aging, revealing a previously unknown anti-aging mechanism and providing a rationale for the co-evolution of cancer resistance and longevity.” See: Delayed ageing through damage protection by the Arf/p53 pathway. (Arf is an upstream regulator of p53.) These mice were not only cancer-resistant, but they had a significantly increased lifespan. In these studies increased p53 activity was associated with a reduction in age-associated DNA damage, and the accumulation of damaged cells.

Explaining the Contradiction.

These examples clearly demonstrate that p53 activity can be increased, providing improved cancer resistance, without adversely affecting lifespan, and in some cases, actually extending lifespan. Therefore, the lifespan reduction seen in the previous examples, must be the result of some other factor, and is not a necessary consequence of the cancer suppressive effects of increased p53 activity per se. There must be something else involved in the methods used to increase p53 activity that explains the reduced lifespan, and the reduction in neural stem cell supply. What do the methodologies of those studies all have in common? Answer: They all used a truncated isoform of p53. Apparently, the reduction in lifespan is the result of the use of this unregulated, truncated variant. As previously mentioned, this truncated isoform is known to antagonize the effects of the regulated, transactivating isoforms, TAp53, TAp63 and TAp73. One way the truncated variant may inactivate the TA isoforms is by directly binding to their transactivation domain, preventing activation and binding to target genes. Mice lacking the p63 gene have shortened lifespans. It is very plausible that the truncated p53 isoform could reduce lifespan by interfering with normal, regulated activity of TAp63. From TAp63: The fountain of youth:

“The mice exhibiting signs of premature aging contain truncated p53 mutants [4,5] while those that display a normal lifespan upregulate p53 by other mechanisms, such as the expression of a p53 transgene in addition to the endogenous p53 alleles or a hypomorphic allele of mdm2 [6,7]. One potential explanation of the discrepancy in the phenotypes of these mice is that TAp63 interacts with point mutant p53 rendering TAp63 functionally inactive. Consequently, mice expressing mutant p53 would exhibit phenotypes similar to those observed in the TAp63-/- mice. Previous studies have shown this to occur in the context of tumorigenesis and metastasis [8,9]. Mice engineered to express point mutants of p53 in Li-Fraumeni Syndrome inactivate p63 and p73 in tumors by binding to them and preventing the transactivation of their target genes [8,9,10]. These mouse models exhibit a metastatic phenotype similar to that observed in p53+/-;p63+/- and p53+/-;p73+/- mice illustrating an intricate relationship between the p53 family members [11,12]. Yet, another unexplored and possible explanation is that expression levels of the p53 family members change in mice that lack one or more of the family members, i.e. gene compensation. Such family member compensation has been observed in other families of genes including the Rb family [13,14,15]. In mouse models expressing abnormally high levels of p53, TAp63 levels may be dampened commensurate with an increase in p53 protein expression. p53 protein levels are known to be high in mice expressing mutated versions of p53 [8,9,10]. Thus, loss of TAp63 in these mouse models may again result in an acceleration of organismal aging.”

p53 is NOT the “central regulator of neurogenesis in the adult mammalian brain”.

As previously mentioned, p73 plays an important role in the maintenance of neurological tissues. Multiple, recent research has demonstrated that p73 maintains neural stem cell pools, not p53 (and most certainly not the truncated p53 variant used in the previously mentioned study). Apparently, the loss of neural stem cells was, once again, due to interference of this truncated p53 variant in the normal, regulated function of TAp73 in maintaining adequate neural stem cell supplies. p73 deficiency results in impaired self renewal and premature neuronal differentiation of mouse neural progenitors independently of p53: “p73 deficiency increases the population of neuronal progenitors ready to differentiate into neurons at the expense of depleting the pool of undifferentiated neurosphere-forming cells. Analysis of the neurogenic niches demonstrated that p73-loss depletes the number of neural-progenitor cells, rendering deficient niches in the adult mice. Altogether, our study identifies TAp73 as a positive regulator of self-renewal with a role in the maintenance of the neurogenic capacity. Thus, proposing p73 as an important player in the development of neurodegenerative diseases and a potential therapeutic target.” See also:

p73 regulates maintenance of neural stem cell

TAp73 acts via the bHLH Hey2 to promote long-term maintenance of neural precursors

p73 is an essential regulator of neural stem cell maintenance in embryonal and adult CNS neurogenesis

p73: A Multifunctional Protein in Neurobiology

Just as TAp73 maintains neural stem cell supplies, TAp63 maintains stem cell supplies in epithelial and other tissues.

TAp63: The fountain of youth:

“TAp63 maintains adult stem cells. The mysterious mechanisms that regulate aging are an area of active research. The induction of senescence or apoptosis in stem and progenitor cells is thought to trigger premature organismal aging [2]. Consistent with this idea, we found that the TAp63-/- mice had a significantly shortened life span compared to its wild-type littermates [1]. These mice exhibited phenotypes associated with premature aging including kyphosis, impaired wound healing, alopecia, epithelial and muscular atrophy, and chronic nephritis. These phenotypes suggest a critical role for TAp63 in the maintenance of adult stem cells in multiple epithelial and non-epithelial tissues. Indeed, we found that TAp63 maintains dermal stem cells by transcriptionally activating the cyclin dependent kinase inhibitor, p57, thereby preventing hyperproliferation of these cells (Figure1A) [1,3]. Similar to the phenotype identified in dermal and epidermal progenitor and stem cells, other adult stem cells in the TAp63-/- mice may be hyperproliferative early in life and through similar senescence mechanisms that we delineated may result in a depletion of these stem cells and premature organismal aging ​(Figure1B) [1].”

TAp63 prevents premature aging by promoting adult stem cell maintenance:

“The cellular mechanisms that regulate the maintenance of adult tissue stem cells are still largely unknown. We show here that the p53 family member, TAp63, is essential for maintenance of epidermal and dermal precursors and that, in its absence, these precursors senesce and skin ages prematurely. Specifically, we have developed a TAp63 conditional knockout mouse and used it to ablate TAp63 in the germline (TAp63(-/-)) or in K14-expressing cells in the basal layer of the epidermis (TAp63(fl/fl);K14cre+). TAp63(-/-) mice age prematurely and develop blisters, skin ulcerations, senescence of hair follicle-associated dermal and epidermal cells, and decreased hair morphogenesis. These phenotypes are likely due to loss of TAp63 in dermal and epidermal precursors since both cell types show defective proliferation, early senescence, and genomic instability. These data indicate that TAp63 serves to maintain adult skin stem cells by regulating cellular senescence and genomic stability, thereby preventing premature tissue aging.”

In what other ways does the p53 family promote longevity?

As we have seen, increased, regulated p53 activity can result in increased longevity, as well as increased cancer resistance. Clearly, one way in which regulated activity of the p53 family may contribute to increased longevity is by maintaining increased stem cell supplies in various bodily tissues. Are there other ways in which the p53 family could contribute to longevity? p53 promotes longevity thru multiple mechanisms and signaling pathways. I may discuss some of these pathways in greater detail in a future post. For now, I will just briefly mention a couple of the many longevity-promoting mechanisms of p53.

Inflammation Reduction.

Aging is characterized by increased local and systemic inflammation. Senescent cells are known to secrete large amounts cytokines (signaling molecules) with multiple harmful effects, including increased inflammation. (ref) The accumulation of senescent cells with aging may, in part, explain age-associated chronic inflammation, which, in turn, contributes to many degenerative conditions, including heart disease, AD, metabolic disorders and cancer. (ref) One of several ways, by which p53 activity reduces inflammation is by directly reducing the harmful secretions of senescent cells. (ref) Suprisingly, p53 also functions to actually suppress cellular senescence, thereby reducing the number of senescent cells excreting harmful cytokines. (ref , ref, ref).

ROS Reduction.

Reactive oxygen species are free radicals which damage cellular structures and interfere with healthy physiologic processes. See: Oxidative Damage. p53 can both increase and decrease ROS. (ref) ROS play an important role in the process of cellular arrest. Mitochondrial energy production depends upon ROS. p53 contributes to controlling the harmful effects of ROS in several ways. p53 regulates mitochondrial function reducing the production of ROS in times of stress, and increases mitochondrial biogenesis. (ref) P53 also maintains mitochondrial DNA, which further reduces ROS. (ref) It is interesting that p53 actually increases ROS within the mitochondria, but generates antioxidants, like manganese superoxide dismutase, in order to prevent the ROS from causing damage outside of the mitochondria. (ref) It is interesting to note that much of the anticancer protection afforded by p53, results directly from its antioxidant function. This is demonstrated by the fact that the tumors in mice lacking p53 were prevented by supplementation of the antioxidant, NAC (a precursor to glutathione). (ref)

Other anti-aging target pathways of p53 activity:

• IGF1-Insulin pathway.

• Akt/mTOR pathway.

• FoxO family of longevity genes.

The Wrap-up.

The p53 family does not cause depletion of stem cell pools. On the contrary, it actively maintains those pools. Moreover, the p53 family appears to promote longevity thru multiple mechanisms/pathways. As with anything known to have multiple, complex functions, in addition to anti-aging effects, p53 undoubtedly also has some pro-aging effects. As I have often said, there are no exclusively “good” or “bad” compounds, or processes. Optimal health is about maintaining balance in the function of regulatory processes. The p53 family is a very promising target for both the prevention of cancer and age-related decline. These two objectives appear to be complementary, not mutually exclusive.

Normal, healthy, physiological processes are regulated by a complex interplay of numerous, neuroendocrinal signaling pathways. Although there are many intermediary signaling events, the fundamental purpose of most signaling pathways is the transfer of regulatory information to and from the central nervous system (CNS). Functional CNS decline precedes the metabolic, reproductive, and cognitive disorders associated with aging. For example, recent advances in brain imaging technology have demonstrated that the structural changes eventually causing Alzeheimer’s Disease (AD), actually take place, long before the first symptoms are observed. Given the central role of the CNS in age-related pathologies, the dynamics of CNS function should, clearly, also be the central focus of anti-aging research. Preventing or slowing age-related changes in the CNS has the potential to maintain healthy physiologic function, as we grow older.

Nonlinear Dynamics and the Loss of Complexity Theory of Aging and Disease

In the past, simple reductionist approaches to the study of physiology have been very productive. However, given the inherent complexity of the dynamics of most physiological processes, including neurological function, future advances in the study of these processes will require the use of nonlinear, whole-systems approaches. (“Nonlinear” means that output is not proportional to input, but varies in more complex, often unexpected, ways.) In Neuroscience, the macro phenomena of cognition, emotion, motor activity, etc. are dependent upon the emergent, collective actions of billions of neurons, each of which is a nonlinear element. In general, physiology is the result of interactions of multiple feedback loops of nonlinear systems. The process of aging can be understood as a reduction in the complexity of these feedback and control systems. See: Loss of ‘Complexity’ and Aging.

Normal, healthy physiological processes function on the edge of “chaos”, which is to say, near a critical point. This allows for greater degree of resilient vitality, and resistance to disruption than systems of a simple periodic, or stochastic nature. The nonlinear dynamics of neural systems facilitate functional adaptation to changing environmental conditions. In contrast, the aging phenotype is characterized by a reduced ability to adapt to stress and trauma reflective of a reduction in complexity of underlying regulatory mechanisms. Such a reduction in complexity may reflect the loss of a component, or the disruption of feedback coupling between components. For example, normal secretion patterns of glucocorticoids, sex steroids, and GH result from shrinkage of the hippocampus, loss of neurons, and declining neurogenesis. The number of dopaminergic neurons also declines with age, accompanied by a corresponding reduction in nigrostriatal signaling, which, in turn, produces such age-related disorders as Parkinson’s disease. See: Dopaminergic Neuronal Loss.

Such changes result in reduced complexity of the signaling dynamics of neural networks, resulting in a reduced adaptive capacity. The increased vulnerability of the aging brain to anoxia and ischemia, is one example of reduced neural adaptive capacity, which appears to be the result of compromised ribonomic ability to selectively translate stress-induced mRNA. See: Towards a dynamical network view of brain ischemia.

Clearly, many age-related disorders are the direct result of alterations in regulatory pathways of the CNS. A loss of neurological complexity as measured in EEGs has been found to characterize patients in a vegetative state. See: Complexity loss in physiological time series of patients in a vegetative state.

Nonlinear methods have been applied to the modeling of circadian rhythms. See: Modeling biological complexity. Many physiological processes depend upon circadian rhythms, which are regulated by a complex network of signaling and feedback mechanisms. Disruption of normal circadian rhythm can have profound health consequences, and is implicated in many diseases of the aging including heart disease, obesity, metabolic syndrome, psychiatric/neurological disorders, and even cancer. Many regulatory factors diminish with age, such as the age-related decrease in melatonin signaling, which results in a loss of regulatory complexity leading to circadian dysfunction.

Systems biology and its application to the understanding of neurological diseases:

“Recent advances in molecular biology, neurobiology, genetics, and imaging have demonstrated important insights about the nature of neurological diseases. However, a comprehensive understanding of their pathogenesis is still lacking. Although reductionism has been successful in enumerating and characterizing the components of most living organisms, it has failed to generate knowledge on how these components interact in complex arrangements to allow and sustain two of the most fundamental properties of the organism as a whole: its fitness, also termed its robustness, and its capacity to evolve. Systems biology complements the classic reductionist approaches in the biomedical sciences by enabling integration of available molecular, physiological, and clinical information in the context of a quantitative framework typically used by engineers. Systems biology employs tools developed in physics and mathematics such as nonlinear dynamics, control theory, and modeling of dynamic systems. The main goal of a systems approach to biology is to solve questions related to the complexity of living systems such as the brain, which cannot be reconciled solely with the currently available tools of molecular biology and genomics. As an example of the utility of this systems biological approach, network-based analyses of genes involved in hereditary ataxias have demonstrated a set of pathways related to RNA splicing, a novel pathogenic mechanism for these diseases. Network-based analysis is also challenging the current nosology of neurological diseases. This new knowledge will contribute to the development of patient-specific therapeutic approaches, bringing the paradigm of personalized medicine one step closer to reality.”

The loss of complexity theory of aging represents a fundamental paradigm shift away from the classical assumptions of normal physiologic homeostasis. By directly challenging the classical assumptions of health and disease, it also points the way to a new class of therapeutic approaches based on whole-system targets, as opposed to treatments based on individual components, in isolation. It is my belief that such large-scale approaches will be necessary to effectively treat aging.

Nonlinear methods have a distinguished history of application in statistical physics. However, their application to physiology is a recent development, often requiring interdisciplinary approaches, since biologists aren’t historically trained in such methods. Despite their limited use, nonlinear methods have already yielded remarkable successes in our understanding of very disparate physiological processes. In addition to the examples previously mentioned, it turns out that the apparently simple, periodic process of a regular heartbeat is actually a complex, multifactorial process on the edge of chaos. See: Nonlinear dynamics of cardiovascular aging. , Chaotic Signatures of Heart Rate Variability. Pathologies of irregular heartbeat, in contrast, are the result of a reduced complexity resulting from a loss of regulatory feedback control mechanisms. Measures of heartbeat chaos have even proven to be the best predictor of mortality in heart patients. See: Heart rate chaos as a mortality predictor in mild to moderate heart failure.

Nonlinear approaches have had success in modeling the complex dynamics of stem cell populations, a process with direct implications for aging. See: Modelling Perspectives on Aging.

Future advances in genetics and epigenetics will undoubtedly rely very heavily upon advanced computational methods. With the mapping of the human genome, many single-gene, Mendelian, diseases have been identified. In fact, I believe it is safe to say that nearly all such disease have already been identified. (There are surely more, however, many extremely rare Mendelian conditions will likely never be identified, simply due to the small number of people affected by them.) See: Rare Genetic Disorders.

However, most diseases do not result from a single gene, but from the complex interaction of many genes (and epigenetic factors), which individually may have little or no correlation with the pathological condition. In order to identify and better understand such multifactorial relationships, Multifactor Dimensionality Reduction (MDR) methods are now being used. For more information on modeling complex genetic interactions, please see the following references. A future discussion will focus, in greater detail, on the role of neuroendocrinal signaling pathways in aging and longevity.

Detecting nonlinear gene-gene interactions using multifactor dimensionality reduction.

Model-based multifactor dimensionality reduction in the presence of noise.

Gene expression model (in)validation by Fourier analysis.

Systems Approaches to Identifying Gene Regulatory Networks in Plants.

Functional data analysis for identifying nonlinear models of gene regulatory networks.

1. hormone replacement therapy says:
   13. May 2011 at 08:13

   Aging is factor which gives ignition to so many diseases and health problems. I know its impossioble to stop this aging process………does it possible to make the aging process to its slow pace? nice post thanks for sharing it

   Adriana

2. Victor says:
   14. May 2011 at 03:11

   Preventing or slowing age-related decline in the CNS, and related signaling pathways, has the potential to slow, or even reverse aging processes. Many encouraging examples of the reversal of age-related decline in physiologic systems, by restoring proper signaling, can be given. Unfortunately, our present understanding of the molecular effects of various pathways is inadequate.

(Expanded version 5/9/2011)

In animal models of longevity, two interventions have consistently been shown to increase lifespan, caloric restriction and suppression of the GH-IGF1-Insulin axis.

It is not possible to merely dismiss animal studies, saying that humans are somehow different, and therefore the results don’t apply, unless you can provide a convincing explanation of how we are different that makes the results from animal studies inapplicable. Besides, longevity and improved health are also associated with humans who have naturally occurring genetic mutations resulting in suppression of these hormones pathways.

Virtually all mice who lack the IGF1 receptor die at birth; some mice who have the IGF1R, but lack IGF1 survive birth, but these survivors suffer extreme developmental abnormalities, achieving less than half their normal weight: Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 1993. Clearly, both IGF1 and its receptor are necessary for survival and healthy development. The same is true for GH. In a 2002 study, for example, rats who were heterozygous (only had one copy) in an anti-sense GH transgene displayed increased longevity, while homozygous rats (who had two copies of the transgene) showed decreased longevity. An anti-sense gene is one that reduces expression of the target GH gene. (Anti-sense genes work by creating a complementary mRNA that can bind to the target mRNA, effectively canceling it out.) In other words, a mild reduction in GH expression increased lifespan, while a stronger reduction was counterproductive, and actually decreased lifespan. Yes, some GH expression is important, but too much is counterproductive. What is the optimal amount? We have only one way to answer this question, by looking at the relevant studies and examining the data. See Life Span Extension by Reduction in Growth Hormone-Insulin-Like Growth Factor-1 Axis in a Transgenic Rat Model.

The point I wish to convey is that there are no good or bad hormones, it is similarly incorrect to refer to certain kinds of cholesterol as “good” and other kinds as “bad.” More about cholesterol in a future discussion. All compounds and physiological pathways have a function and purpose. However, their effects need to be kept in balance, within certain optimal ranges for improved health outcomes; even though we may not know what those optimal ranges are, and they may vary over the course of the human life cycle.

One interesting study discusses a group of female centenarians with elevated plasma IGF1 levels. However, their increased longevity has nothing to do with their increased IGF1 levels. In fact, they did not have increased IGF1 signaling, at all. They experienced impaired or reduced IGF1 signaling due to a defective IGF1 receptor with decreased ligand binding. This reduced IGF1 signaling resulted in decreased stature as well as increased plasma IGF1 levels. (More IGF1 remained in the plasma, since it could not bind as efficiently to the cellular receptors.) See Functionally significant insulin-like growth factor I receptor mutations in centenarians.

A similar, but even more extreme effect occurred in individuals with a mutation that caused an alteration in the IGF1 protein sequence. This altered IGF1 had a 90% reduced receptor-binding affinity, causing extremely elevated plasma IGF1 levels. This altered IGF1 resulted in pre- and post- natal growth retardation, deafness, and mental retardation, illustrating the importance of IGF1 for normal fetal, as well as postnatal development. (The important role of IGF1, for prenatal development had already been well established, before this study was published.) These examples illustrate that while one mutation resulted in extended lifespan, another mutation with similar, but more extreme effects had very harmful outcome. See Homozygous and Heterozygous Expression of a Novel Insulin-Like Growth Factor-I Mutation.

This body of research focuses on investigating the various health and longevity effects of different, specific, alterations in GH-IGF1-I signaling pathways. Usually the alteration involves an impairment, of varying degree, in signaling; although, in some cases, it involves an over-expression in signaling. In all cases, the results reveal important information about the underlying mechanisms of action of these hormone-receptor signaling pathways, regardless of whether the change is brought about by an alteration in one of the primary hormones, a receptor, or other downstream proteins, i.e. p66, KLOTHO, etc. Some of these studies illustrate important interactions between pathways associated with health and longevity. One, for example, discusses important mechanisms of interaction or interplay between IGF1 signaling and ROS signaling pathways. Radical Oxygen Species have very clear implications for health and aging mechanisms. See Insulin/IGF-1 and ROS signaling pathway cross-talk in aging and longevity determination.

In another interesting study, PAPP-A knockout mice showed dramatically increased healthspan, increased lifespan with a decrease in pathologies such as cancer and heart disease, without any change in circulating GH, IGF1, glucose, or insulin. Loss of pregnancy-associated plasma protein A extends lifespan in mice. See Genetic Deletion of Pregnancy-Associated Plasma Protein-A Is Associated With Resistance to Atherosclerotic Lesion Development. PAPP-A is a protease enzyme that cleaves, or breaks up, IGF1 binding proteins. This is significant because PAPP-A represents a possible way to modify IGF1 signaling, without affecting GH signaling.

In some cases, reduced IGF1 signaling does not improve health or increase lifespan. In other cases, increased IGF1 signaling increases healthspan. In one interesting case, for example, tissue-dependent effects are revealed, when over-expression of IGF1 signaling in cardiac tissue increases longevity and cardiac health, even reversing cardiac dysfunction: See CARDIAC-SPECIFIC OVEREXPRESSION OF IGF-1—.

Here is a further sampling of excerpts from some of the relevant literature:

Life span extension by reduction of the growth hormone-insulin-like growth factor-1 axis: relation to caloric restriction: “A reduced growth hormone (GH)-insulin-like growth factor (IGF)-1 axis is associated with an extension of lifespan in laboratory rodents. Several phenotypes of such animal models resemble those induced by caloric restriction (CR). Using a transgenic male Wistar rat model whose GH-IGF-1 axis was moderately suppressed by overexpression of the antisense GH transgene (tg), we elucidated a relationship between the effects of a reduced GH-IGF-1 axis and CR for some biomarkers of aging, lifespan, and pathologies. Heterozygous (tg/-) rats fed ad libitum (AL) had a dwarf phenotype similar to that of control nontransgenic (-/-) rats subjected to 30% CR from 6 wk of age. Both the reduced GH-IGF-1 axis and CR extended lifespan to a similar extent, although the effect of CR seemed to be greater. There was an additive effect of CR to lifespan extension when tg/- rats were subjected to CR. Pathologic analyses indicated that the preventive effect of CR on selected diseases was greater than that of the reduced GH-IGF-1 axis. The present study suggests that CR affects aging and longevity by mechanisms other than suppression of the GH-IGF-1 axis, although CR might exhibit its effects partly through the reduced GH-IGF-1 axis.“

The new biology of ageing: “Perhaps the single most important advance in ageing research in recent years has been discovery of mutations in single genes that extend the lifespan of laboratory animals. They first came to light as a result of a systematic chemical mutagenesis screen for lifespan-extending mutations in C. elegans (Klass 1983). Subsequent work with these mutations (Friedman & Johnson 1988), and further screening (Kenyon et al. 1993), revealed that it was possible to double the lifespan of the worm with a mutation in a single gene. Furthermore, rather than solely prolonging the moribund period at the end of the life, the mutations caused the worms to remain healthy and youthful for longer (Kenyon et al. 1993). The mutated genes were discovered to encode components of an invertebrate insulin/insulin-like growth-factor-like signalling (IIS) pathway (Kimura et al. 1997; Lin et al. 1997; Ogg et al. 1997). These findings came as a considerable surprise, because a signalling pathway previously associated with control of growth and metabolism in mammals now turned out to play a role in determination of lifespan in a distantly related invertebrate.”

Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models: “Overwhelmingly, the evidence suggests that a reduction in GH/IGF-1 signaling in vertebrates or its homologous pathways in invertebrates extends lifespan as compared to control or normal siblings. . . Insulin and insulin-like growth factor 1 (IGF-1)-like signaling and its downstream intracellular signaling molecules have been shown to be associated with lifespan in fruit flies and nematodes. More recently, mammalian models with reduced growth hormone (GH) and/or IGF-1 signaling have also been shown to have extended lifespans as compared to control siblings. Importantly, this research has also shown that these genetic alterations can keep the animals healthy and disease-free for longer periods and can alleviate specific age-related pathologies similar to what is observed for CR individuals. Thus, these mutations may not only extend lifespan but may also improve healthspan, the general health and quality of life of an organism as it ages. In this review, we will provide an overview of how the manipulation of the GH/IGF-axis influences lifespan, highlight the invertebrate and vertebrate animal models with altered lifespan due to modifications to the GH/IGF-1 signaling cascade or homologous pathways, and discuss the basic phenotypic characteristics and healthspan of these models.“

How does insulin/IGF signalling control lifespan in worms,  flies and mice? “Ageing research has been revolutionized by the use of model organisms to discover genetic alterations that can extend lifespan. In the last 5 years alone, it has become apparent that single gene mutations in the insulin and insulin-like growth-factor signalling pathways can lengthen lifespan in worms, flies and mice, implying evolutionary conservation of mechanisms. Importantly, this research has also shown that these mutations can keep the animals healthy and disease-free for longer and can alleviate specific ageing-related pathologies. These findings are striking in view of the negative effects that disruption of these signalling pathways can also produce.  Here, we summarize the body of work that has lead to these discoveries and point out areas of interest for future work in characterizing the genetic, molecular and biochemical details of the mechanisms to achieving a longer and healthier life.”

Signal pathway of insulin and insulin-like growth factor 1 (IGF-1) as a potential regulator of lifespan: “The experimental material accumulated for two decades allows concluding that regulation of lifespan has hormonal control based on the evolutionary conservative insulin/IGF-1 receptor signal pathway. Data obtained on the commonly accepted models of longevity – nematode Caenorhabditis elegans, Drosophila Drosophila melanogaster, and rodents – demonstrate that reduction of the insulin/IGF- 1 signal pathway leads to an increase of the lifespan. There is shown involvement of the longevity mechanism of a large group of genes whose products perform control of metabolism, alimentary behavior, reproduction, resistance to oxidative stress. Discussed in this review are current concepts of the insulin/IGF-1 signal system as a regulatory “longevity module” and of its possible role in prolongation of life in the higher vertebrates, including human.”

Single-gene mutations and healthy ageing in mammals: “Studies of the effects of single-gene mutations on longevity in Caenorhabditis elegans, Drosophila melanogaster and Mus musculus identified homologous, highly conserved signalling pathways that influence ageing. In each of these very distantly related species, single mutations which lead-directly or indirectly-to reduced insulin, insulin-like growth factor (IGF) or insulin/IGF-like signalling (IIS) can produce significant increases in both average and maximal lifespan. In mice, most of the life-extending mutations described to date reduce somatotropic (growth hormone (GH) and IGF-1) signalling. The reported extensions of longevity are most robust in GH-deficient and GH-resistant mice, while suppression of somatotropic signalling ‘downstream’ of the GH receptor produces effects that are generally smaller and often limited to female animals. This could be due to GH influencing ageing by both IGF-1-mediated and IGF-1-independent mechanisms. In mutants that have been examined in some detail, increased longevity is associated with various indices of delayed ageing and extended ‘healthspan’. The mechanisms that probably underlie the extension of both lifespan and healthspan of these animals include increased stress resistance, improved antioxidant defences, alterations in insulin signalling (e.g. hypoinsulinaemia combined with improved insulin sensitivity in some mutants and insulin resistance in others), a shift from pro- to anti-inflammatory profile of circulating adipokines, reduced mammalian target of rapamycin-mediated translation and altered mitochondrial function including greater utilization of lipids when compared with carbohydrates.”

Mammalian models of extended healthy lifespan: “Specific mutations in the insulin/insulin-like growth factor (IGF) signalling (IIS) pathway extend lifespan in model organisms [7–9,13,16–19]. Polymorphisms in several IIS and growth hormone (GH)-related genes correlate with human longevity [20–22], and attenuated IIS may underlie the long life of GH/GH receptor-deficient dwarf mice (e.g. Ames (Prop1df/df), Snell (Pit1dw/dw), Little (Ghrhrlit/lit), growth hormone receptor knockout (GHR-KO) [23]). The target of rapamycin (TOR) pathway also plays a key and conserved role in longevity control [24–29]. It is clear that understanding how exactly the IIS, GH and mTOR signalling pathways interact with one another to increase lifespan and healthspan is a key challenge to future research.”

Replication of Extended Lifespan Phenotype in Mice with Deletion of Insulin Receptor Substrate 1: “We previously reported that global deletion of insulin receptor substrate protein 1 (Irs1) extends lifespan and increases resistance to several age-related pathologies in female mice. However, no effect on lifespan was observed in male Irs1 null mice. We suggested at the time that the lack of any effect in males might have been due to a sample size issue. While such lifespan studies are essential to our understanding of the aging process, they are generally based on survival curves derived from single experiments, primarily due to time and economic constraints. Consequently, the robustness of such findings as a basis for further investigation has been questioned. We have therefore measured lifespan in a second, separate cohort of Irs1 null female mice, and show that, consistent with our previous finding, global deletion of Irs1 significantly extends lifespan in female mice. In addition, an augmented and completed study demonstrates lifespan extension in male Irs1 null mice. Therefore, we show that reduced IRS1-dependent signalling is a robust mechanism through which mammalian lifespan can be modulated.”

Effects of a growth hormone-releasing hormone antagonist on telomerase activity, oxidative stress, longevity, and aging in mice: “Here, we determined the effects of treatment with the GH-releasing hormone (GHRH) receptor antagonist MZ-5-156 on aging in SAMP8 mice, a strain that develops with aging cognitive deficits and has a shortened life expectancy. Starting at age 10 mo, mice received daily s.c. injections of 10 μg/mouse of MZ-5-156. Mice treated for 4 mo with MZ-5-156 showed increased telomerase activity, improvement in some measures of oxidative stress in brain, and improved pole balance, but no change in muscle strength. MZ-5-156 improved cognition after 2 mo and 4 mo, but not after 7 mo of treatment (ages 12, 14 mo, and 17 mo, respectively). Mean life expectancy increased by 8 wk with no increase in maximal life span, and tumor incidence decreased from 10 to 1.7%. These results show that treatment with a GHRH antagonist has positive effects on some aspects of aging, including an increase in telomerase activity.”

By Victor 

Recent scientific research suggests that modern ambient living conditions may be an important factor in the worldwide obesity epidemic. One reason for this is related to brown adipose tissue (BAT). Brown fat tissue or BAT has the opposite function of white fat tissue; instead of storing fat, it burns it. BAT makes up 25% of the body mass of new-born infants, who need this fat type to maintain their body temperature. Hibernating animals also use BAT to maintain body temperature during long periods of exposure to cold. Only recently have researchers discovered the importance of BAT in adult humans. BAT uses a specialized protein called “UPC1” to generate heat by “uncoupling” thermogenesis (heat generation) from cellular respiration which results in the production of ATP. The body uses ATP for most of its energy needs. However, uncoupling causes cells to “lose” energy; the “lost” energy (meaning it doesn’t produce ATP) results in the cellular production of heat. This process of uncoupling burns up fat more rapidly than does using fat to produce ATP.

What does all of this have to do with modern ambient living conditions?

The first person to blame for the current obesity epidemic may well be Thomas Edison. The circadian hormone, melatonin regulates both the amount and activity of BAT; and melatonin production is regulated by exposure to light. During the winter season, when there is less daylight, the body increases melatonin production, increasing the amount and activity of BAT, burning greater amounts of fat, presumably to help stay warm during the cold winter months. With exposure to modern lighting humans produce less melatonin, and burn less fat, leading obesity. Why not just take supplemental melatonin? This may not be a bad idea; but it is unlikely to be an adequate substitute for darkness.

See: (2011) Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity.

What about ambient temperature?

BAT activity is very responsive to changes in ambient temperature.

See:

(2009)  Cold-Activated Brown Adipose Tissue in Healthy Men

(2009) Brown Adipose Tissue and Seasonal Variation in Humans

(2010) Identification and Importance of Brown Adipose Tissue in Adult Humans

This fact has led researchers to suspect that another important factor in the current obesity epidemic is modern indoor heating. Very few people are presently subjected to seasonal cold conditions, since virtually all modern dwellings and workplaces have climate control which provides year-round, comfortable, warm temperatures.

See:

(2010) Is thermogenesis a significant causal factor in preventing the “globesity” epidemic?

(2011) Rising indoor winter temperatures linked to obesity?

So, to lose those extra pounds, turn down the thermostat, and turn off the lights.

I have invited Victor to be an Associate Researcher-Writer for this blog and expect that one or two of his first blog entries will appear online today.  Victor responded to my recent Call for associate researcher-writers by submitting a number of candidate blog entries.  Those items and correspondence with him convinced me that Victor has what it takes to extend the coverage of this blog in scope and depth while maintaining and improving its quality: in-depth knowledge of key science areas relevant to longevity, scientific integrity, an interest in scouring the ever-changing literature, a probing mind seeking to investigate new developments for their possibilities, a passion for discovery, an attention to detail,  an interest in communicating, and a capability to write clearly.  Victor’s blog entries will appear with minimum or no editing on my part.  To the extent that he offers views and opinions, they will be his own and may be different than mine.  If I feel a need to comment on anything he says I will do so via blog comments just like any other blog reader. 

We are in the midst of a long-term shift in paradigms related to the essence of how we take care of ourselves as we live until we die.  The shift is from the predominant current model which we call healthcare to a new model which I call wellness-longevity.  I contrast these models and discuss specific examples of the multiple ways in which the new model is slowly emerging.

Healthcare

“Health care is the diagnosis, treatment and prevention of disease, illness, injury, and other physical and mental impairments in humans. Health care is delivered by practitioners in medicine, chiropractic, dentistry, nursing, pharmacy, allied health, and other care providers.” Healthcare in advanced countries is mainly based on a medical model, a repair-shop model primarily focused on trying to cure people or allow them to be functional after they obviously get sick or become debilitated.  This is often an inefficient process and for many situations like age-related dementia and several cancers works poorly or not at all.   

Healthcare is an extremely large and diverse industry.   According to an overview of the healthcare industry: “The United States of America has one of the largest medical and healthcare industries in the world, followed by Switzerland and Germany. The USA’s medical industry comprises of more than 750,000 physicians and 5,200 hospitals. USA witnesses approximately 3.8 million inpatient visits and 20 million outpatients visit on a daily basis. Furthermore, the United States of America has the largest workforce i.e. one in every 11 US residents employed in the health care business.” Important additional components of the healthcare industry includes the pharmaceutical industry, many biotech companies, medical equipment manufacturers, government agencies like the National Institutes of Health and the FDA, multiple State health and regulatory agencies, health insurance companies, the armed services medical corps, and university schools of medicine, dentistry and public health.

The economics of healthcare are staggering.   “The Global prescription drug market was $550 billion in the year 2006. Also, the total health care expenditures across the world were $4.5 trillion last year. Of which, US solely account for $ 2.2 trillion, $ 2 trillion in OECD countries and remaining $ 0.3 in other countries of the world. Learn about the challenges for the medical industry in the article ‘2009 Financial Crisis: Top 9 Issues for Health Industries(ref).” “Dramatic figures in the CMS report show that health care accounted for 17.3% of the U.S. economy in 2009(ref).” (I would not be surprised if the number is now up to 20%) “The increase in health spending, from $2.34 trillion in 2008 to $2.47 trillion in 2009, was the largest one-year jump since 1960. CMS predicts total U.S. health spending in 2019 will be $4.5 trillion.” Breakdown of US national health care expenditures can be found here.

Besides becoming ever-more and more expensive and possibly unworkable, the health care model often produces poor results.  If a car is poorly maintained, by the time blue smoke is coming out of the exhaust and oil is being burned, the rings and valves in the engine could already be ruined and the car not economically repairable.  Simple maintenance and regular oil and oil filter changes can largely avert the problem.  If the body of an obese elderly person is poorly taken care of with insufficient exercise and poor diet, by the time active signs of diabetes show up the body’s metabolic systems could have so remodeled themselves that cure is impossible.  Simple preventative maintenance including a program of exercise and good diet can also frequently prevent diabetes from manifesting itself.

Wellness-longevity

Wellness-longevity is a new paradigm that subsumes health care but goes far beyond it.  It is a paradigm that has been discussed for a long time but that is only now starting to become manifest. Wellness-longevity is not focused on sickness but rather on maintenance of health and longevity.  It is comparable to preventive maintenance where steps are taken to prevent debility or sickness sufficiently in advance so that debility or sickness becomes relatively scarce.  While important aspects of wellness-longevity are captured in the traditional idea of preventative medicine, wellness-longevity goes much further in expectations for ever-enhanced longevity, personal productivity and transformed lifestyles.

Airliner safety maintenance – a working model of wellness and longevity

Prodded by governments, long ago commercial airlines industry decided to adopt a wellness-longevity model for their airplanes.   When air crashes occur it is usually because that model has not been followed diligently.  The decision to make this model universal was based on safety and economics.  If the airlines industry were to follow a model like our healthcare systems where most problems are addressed only after they became manifest, we would probably be hearing about dozens of crashed airplanes every week. 

It is useful to look at the airlines wellness-longevity model and see how it works and how effective it is.  As it turns out, many aspects of the model can be applied to human wellness-longevity.  The objective of the airliner safety program is to assure that every working airliner is a safe to fly in as a new one. Even if the aircraft is 50 years old.  So different aircraft can compete in terms of efficiency, range, comfort, etc., but are basically the same in terms of passenger safety.

Details of the wellness-longevity program for aircraft are contained in this Maintenance: Airplane and Airline FAQ.  Aspects of the program include limitations on the numbers of flights and flight hours between inspection, multiple levels of preventative maintenance including before every flight, maintenance of detailed computer records on the history of every component in the aircraft, a schedule of frequent inspections of multiple kinds, computerized logs of multiple kinds, definitions of when parts must be overhauled or replaced, documentation of every problem observed no matter how slight, multiple monitoring systems built into the aircraft, centralized reporting of problems with information shared across airlines, government-mandated upgrades and constant manufacturer improvement of components.  If and when accidents occur there is careful analysis of what happened and identification of possible corrective actions. 

Clearly there are some things in this program like stripping out all the parts and maintaining or replacing  them individually can’t be done with humans.  But many other aspects of the program may well be worth emulating.  For example: “AIRWORTHINESS DIRECTIVES (A.D.’s)  As a further double-check that the commercial airline fleet is meticulously maintained, the FAA has set up an information system where maintenance reliability data can be shared by the airlines. If certain important components of an aircraft such as the engines, flight controls, hydraulic system, brakes, etc. should fail during flight, the individual airline must notify the FAA, which forwards the data to all airlines. This serves as an alert to the airlines so their inspection schedule can be altered as necessary. If another failure should occur with that same component, the FAA can order a mandatory change in the inspection timetable by issuing an Airworthiness Directive. Regardless of how soon the next preventive maintenance or overhaul is scheduled, an A.D. requires immediate action in the time allowed by the FAA, even if it requires removing an airplane from service. If an unsafe condition exists, an A.D. will be issued that will ground an entire fleet of airplanes, until a safe fix can be found(ref).” 

Despite these rules, adherence to them by different airlines vary.  Five-year safety records for different airlines can be found here.  The main point is that even for the worst airlines, air travel is by far the safest form of travel on a per-mile basis.  Accidents are very rare and not the norm.  This chart shows how the vast majority of important airlines in the world have not had a fatal accident in the last 10 years.  Why can’t we do something like this for people?  I am convinced we can and will and are already started on the way to getting there.

 A human model for wellness-longevity

 What the human model for wellness-longevity will look like in the long term is unknown.  I have, however, already provided a fairly thorough vision of it in the recent blog entry The 2011 Bio-IT World Conference & Expo – On the way to Personalized Predictive Preventative Participatory Medicine and in last  year’s blog entry Harnessing the engines of finance and commerce for life-extension.  Reading those blog entries you will see that there is a striking similarity to what I envisage and what the airlines are doing:  pursuing a healthy lifestyle in every regard, regular preventative maintenance, maximum use of information systems, maintaining very detailed personalized records (whether personalized to an individual or to a specific aircraft), strictly following a number of wellness regimens, identification and use of biomarkers (performance and wear indicators in the case of aircraft parts),  widespread sharing of information, sharing of information among relevant parties (hospitals, patients, doctors for people, different airlines; manufacturers and government agencies for aircraft), prompt analysis of breakdowns and warnings to others, etc.

The benefits of going beyond healthcare to wellness-longevity paradigm

The healthcare paradigm by itself is broken, obsolete, and produces poor results.   Despite the fact that the US spends more per capita on healthcare than leading European countries that put somewhat more emphasis on wellness, we trail those countries miserably in multiple measures of health and trail them in longevity.  See the blog US falling behind in longevity increases – why?    Curing diseases after they occur is vastly more difficult than preventing disease occurrences in the first place.  Further, many diseases themselves create multiple forms of collateral damage, particularly in elderly patients.  So a serious disease late in life often leads to a down-hill cascade of events leading soon to disability and death.  And many diseases of old age like Alzheimer’s disease have proven themselves to be resistant to the possibility of “cure” despite tens of billions of dollars spent researching them.

For individuals, benefits of moving to the new paradigm are a longer healthier life.  For health plans and health insurance companies, immediate benefits include drastically lowered health care costs.  The same is true for state and federal governments and for corporations that provide health care coverage for employees.  And along with lowered health care costs go increased productivity of healthier longer-lived people. 

Examples of the emerging wellness-longevity paradigm

Expressions of the new wellness-longevity paradigm are showing up in multiple forms.  I mention only a few of the many things happening.

SilverSneakers

 “The SilverSneakers® Fitness Program is an innovative health, exercise and wellness program helping older adults live healthy, active lifestyles.”  The program is offered through health plans. “The Silver Sneakers Fitness Program brings yoga, Pilates, aquatic and cardio circuit classes to older Americans at 10,000 locations in 50 states. “We have done a lot to educate,” said Stephanie Wong, spokesperson for Silver Sneakers. “Particularly among 70- and 80-year olds who have not been members of a gym, it’s a whole new ball game.”  Brain booster exercises are also on the menu for the Silver Sneaker participant, whose average age is 72. “The longer you can be independent, the more successfully you’re going to age,” Wong said. “If you prevent falling you avoid being transitioned into a senior centre. Physical activity promotes brain health. Recent studies support that(ref).”

  “SilverSneakers is a fun, energizing program that helps older adults take greater control of their health by encouraging physical activity and offering social events. — Unlock the door to greater independence and a healthier life with SilverSneakers. Health plans around the country offer our award-winning program to people who are eligible for Medicare or to group retirees. SilverSneakers provides a fitness center membership to any participating location across the country. This great benefit includes:

·        access to conditioning classes, exercise equipment, pool, sauna and other available amenities

·        customized SilverSneakers classes designed exclusively for older adults who want to improve their strength, flexibility, balance and endurance

·        health education seminars and other events that promote the benefits of a healthy lifestyle

·        a specially trained Senior AdvisorSM at the fitness center to introduce you to SilverSneakers and help you get started

·        member-only access to online support that can help you lose weight, quit smoking or reduce your stress

·        SilverSneakers Steps for members without convenient access to a location(ref)”

Let’s Move

Lest it be thought that the emerging wellness-longevity paradigm is concerned only with seniors Let’s Move is a fitness thrust oriented to children.  Let’s Move is a campaign designed to reduce the incidence of childhood obesity being promoted by Michelle Obama.  As such it is oriented to people at the opposite end of age demographics.  It is concerned with promotion of healthy food and nutrition as well as regular exercise as tools for preventing obesity and creating a healthier generation of younger Americans at all economic levels. 

PreventObesity.net

 PreventObesity.net is an initiative designed to foster networking to support the prevention of childhood obesity. “We offer free services to support leaders and organizers as you work to change policies and environments to help children and families eat well and move more, especially in communities at highest risk for obesity.” – “Driven by a belief that technology offers an opportunity to tap the talents, creativity, expertise and energy of potential collaborators, the Robert Wood Johnson Foundation (RWJF) launched PreventObesity.net to harness the power of online networks to reverse the childhood obesity epidemic.

 Netcentric

RWJF has engaged with Netcentric Campaigns to create and implement networking strategies that support the Foundation, the Robert Wood Johnson Foundation Center to Prevent Childhood Obesity, other RWJF-funded national programs and others working in the field. Netcentric has supported other health-related online campaigns such as the Health Care for America Now (HCAN) campaign.

Entrepreneurial ventures

Because of institutional rigidities, the new wellness-longevity paradigm may be moved along swiftly by entrepreneurial ventures.  Here are a few examples:

23andMe

23andme is a $207 personal genotyping service oriented toward ordinary people and the wellness rather than the healthcare market.  Using a DNA chip, the service scans the saliva of a customer to look for the presence of about a million SNPs that are spread across the entire genome. “A single-nucleotide polymorphism (SNP, pronounced snip) is a DNA sequence variation occurring when a single nucleotide — A, T, C, or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes in an individual(ref)”  The SNPs looked for are ones known to be “tag” SNPs correlated with ones that have important disease, hereditary and other associations.  “23andMe is a retail DNA testing service providing information and tools for consumers to learn about and explore their DNA. We utilize the Illumina OmniExpress Plus Research Use Only Chip which has been customized for use in all of our products and services by 23andMe. All of the laboratory testing for 23andMe is done in a CLIA-certified laboratory.”  Among things scanned for are carrier status for 24 inherited conditions, 19 kinds of drug responses, 50 traits and disease risk for 100 conditions.  Output is a personalized profile with much interpretative and educational material. 

The 23andMe service includes a one-year Personal Genome Service  subscription which includes updates about yourself, browsable raw data, discounts on future platforms, secure storage, and alerts when relatives are discovered.   

The 23andMe service is careful to point out that the genotyping does not constitute a diagnostic test: a) because the 23andme service it is not FDA approved, b) because the gene chips involved are less reliable than much more expensive ones, c) because the number of SNPs scanned for is a small fraction of those known to show up in the whole human genome, d) because many of the disease and other associations indicated by the presence of SNPs are weak indicating only a probabilistic propensity,  and perhaps most critically, e) because interpretations of SNPs are only as good as the association studies that provide such interpretations.  Rather, 23andMe is a direct-to-consumer wellness-longevity service that is in the genotyping area where the medical profession has been slow to respond.

MDVIP

MDVIP is a network of primary care doctors who deliver both personalized wellness services as well as conventional medical services in a service model defined by MDVIP.  Current membership includes 450 doctors in 33 states.  While an average family practitioner may have 2,400 patients, MDVIP limits the load to 600 patients per doctor and requires all participating doctors to follow its model.  Focus is on personalized care, detection and early prevention.   “When it comes to your health, you deserve an equal partner. — With the right support, you have the power to transform your life. That’s why at MDVIP, we’ve created a unique approach to healthcare that puts you, your health and your needs first. You’ll have the chance to create a strong, compassionate partnership with your personal doctor – a relationship that will help you reach your wellness goals and become an advocate for healthy living in your community. — Our approach departs from traditional healthcare systems that reward doctors for seeing as many patients as possible. Instead, we give your doctor the time and freedom to get to know you, your lifestyle and your current health. He or she can then offer you carefully thought out, comprehensive health plans with long-term health benefits. Your doctor can follow up with you on a regular basis to help prevent any new medical issues from going undetected.”  Patients pay from $1,500 to $1,800 per year to their MDVIP doctor for wellness services not covered by insurance.  This makes joining MDVIP attractive to primary care doctors who tend to be overworked and underpaid when compared to their medical-specialty peers. 

Apparently the MDVIP model is successful in both providing wellness and reducing medical costs, reducing hospital utilization by 75% in the case of medicare patients, reducing hospital utilization by 65% in the case of privately-insured patients.  This is according to information provided me by MDVIP. I plan to do a separate blog entry on MDVIP. 

Shape up the nation

The web service shapeupthenation.com seeks to utilize social networking for personal achievement of health objectives.  The concept is connecting with people you trust to help you fulfill your health goals.  “Shapeupthenation offers a web platform that can be used by health plans to achieve a number of objectives including “Embrace Social Networking: Health plans across the nation are trying to figure out their social networking strategy. Our platform harnesses the power of trusted social networks to help you achieve your business objectives using the latest and most innovative technology. Don’t keep putting it off — it’s time to get started. — Engage Members: Healthy, engaged members are every health plan’s dream. Let us help you build positive relationships with your members and bring them together with your company as the central partner in their health.  Build Value for Employers: Your employer groups are desperately seeking ways to control rising health care costs and boost morale, productivity, and retention. Help them by offering a proven way to change employee behavior and transform company culture.  Reduce Costs: Our evidence–based program is proven to help members increase exercise and lose weight. In fact, a recent study shows that the average participant loses one Body Mass Index point, which translates to a $202.30 reduction in claims annually.  Help Community: Some health plans are looking beyond their current membership and wondering how they can play a role in helping to promote healthy lifestyles on a community–wide basis. We have experience in running large–scale community wellness programs and can do the same for you.”

Smartphone apps

Perhaps nowhere can small-scale entrepreneurial initiatives for wellness-longevity be seen more dramatically than in the swelling list of health-fitness apps for iPhones and Android phones.  There are hundreds of such apps out there, mainly supported by small entrepreneurial companies. 

Smartphones have orientation and motion sensors that can help determine your kinds and levels of movement.  They have GPS and cell-tower location sensing that allows you, for example, to track an exercise path in the woods.  They have cameras that can be used to read bar codes on food packages and monitor heart rates.  And they have Bluetooth capability that enables them to link to Bluetooth-enabled body sensors.  They can listen to and interpret what you say and talk back to you.  They are usually with you.  They can keep you in constant connection with multiple health databases. And the data related to the apps are available both wirelessly and online via computers and tablet devices.

I find these apps fascinating and plan to do a blog entry on them in the near future.  For now, Android health and fitness marketplace apps are here.  You can check out the “8 best android apps for health and fitness,” the “50 Coolest Fitness and Health Apps for the iPhone,”  and “100 Fabulous iPhone Apps for Your Health and Fitness.” Yesterday, I started using a couple of apps on my Google Android phone, both of which were downloaded for free.  One is called Myfitnesspal, an application allows the user to set and track weight goals by detailed monitoring of daily diet and exercise.   It knows calorie contents of many foods.  Online access is available either via computer or Android phone.  Another amazing app I have started using measures heart rate using your my phone’s camera.  It is called Instant Heart Rate and has been downloaded 250,000 times.

We are in interesting times!  I invite my blog readers to comment on these and other wellness-longevity initiatives you may find to be particularly interesting.

Multiple factors are implicated in age-related physical brain changes and normal decline of memory and brain functioning.  Continuing research is clarifying the relationships among these factors with new insights coming into focus.  I report here on some of those relationships as well as interventions that can avert or even possibly reverse age-related cognitive or memory decline.  This blog entry particularly deals with what is going on in the aging hippocampus and links up a number of topics I have discussed previously in this blog and in my longevity treatise –  neurogenesis,  BDNF, exercise, resveratrol, and curcumin. 

About the hippocampus and aging

“The hippocampus is a major component of the brains of humans and other mammals. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Like the cerebral cortex, with which it is closely associated, it is a paired structure, with mirror-image halves in the left and right sides of the brain. In humans and other primates, the hippocampus is located inside the medial temporal lobe, beneath the cortical surface.  It contains two main interlocking parts: Ammon’s horn and the dentate gyrus. — Since different neuronal cell types are neatly organized into layers in the hippocampus, it has frequently been used as a model system for studying neurophysiology. The form of neural plasticity known as long-term potentiation (LTP) was first discovered to occur in the hippocampus and has often been studied in this structure. LTP is widely believed to be one of the main neural mechanisms by which memory is stored in the brain. (ref).”

Brain cell renewal depends on neurogenesis due to differentiation of neural stem cells mainly in the hippocampus and cell migration.  The process goes on throughout life.

The rate of neurogenesis tends to decline with aging and maintenance of an adequate level of neurogenesis is another important consideration in keeping an aging brain vital. 

From the August 2010 blog post Neurogenesis, curcumin and longevity: “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.”

The 2009 publication Endogenous regulation of neural stem cells in the adult mammalian brain relates: “Tissue-specific stem cells replenish organs by replacing cells lost due to tears and wears or injury throughout life. Long considered as an exception to this rule, the adult mammalian brain has consistently been found to possess stem cells that ensure neurogenesis. Neural stem cells persist within the subventricular zone bordering the lateral ventricles of the brain. Constitutively, neural stem cells proliferate and produce a continuous supply of new neurons that migrate towards the olfactory bulb where they ensure turnover of interneurons. Owing to their potential clinical use for the treatment of neurodegenerative diseases, the factors that control proliferation, self-renewal and differentiation of neural stem cells have received increasing interest. These studies have unraveled that the cellular dynamic within the subventricular zone is tightly controlled by astrocytes and endothelial cells that neighbor neural stem cells. These neighboring cells produce substrate-bound and soluble factors that make up a specialized microenvironment named the neurogenic niche. The equilibrium between neural stem cells activity and quiescence is adjusted by neurons located in remote brain areas that adapt neuron production to physiological and pathological constraints. Brain injury or neurodegenerative diseases affect neural stem cells proliferation, differentiation and migration suggesting that neural stem cells are involved in brain self-repair. Understanding the endogenous mechanisms that regulate neural stem cells will help to replenish cellular constituents lost by injury and thereby allow an effective development of neural stem cells based therapies of brain diseases.”

The 2009 publication Cell migration in the normal and pathological postnatal mammalian brain relates “In the developing brain, cell migration is a crucial process for structural organization, and is therefore highly regulated to allow the correct formation of complex networks, wiring neurons, and glia. In the early postnatal brain, late developmental processes such as the production and migration of astrocyte and oligodendrocyte progenitors still occur. Although the brain is completely formed and structured few weeks after birth, it maintains a degree of plasticity throughout life, including axonal remodeling, synaptogenesis, but also neural cell birth, migration and integration. The subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus are the two main neurogenic niches in the adult brain. Neural stem cells reside in these structures and produce progenitors that migrate toward their ultimate location: the olfactory bulb and granular cell layer of the DG respectively. The aim of this review is to synthesize the increasing information concerning the organization, regulation and function of cell migration in a mature brain. In a normal brain, proteins involved in cell-cell or cell-matrix interactions together with secreted proteins acting as chemoattractant or chemorepellant play key roles in the regulation of neural progenitor cell migration. In addition, recent data suggest that gliomas arise from the transformation of neural stem cells or progenitor cells and that glioma cell infiltration recapitulates key aspects of glial progenitor migration. Thus, we will consider glioma migration in the context of progenitor migration. Finally, many observations show that brain lesions and neurological diseases trigger neural stem/progenitor cell activation and migration toward altered structures. The factors involved in such cell migration/recruitment are just beginning to be understood. Inflammation which has long been considered as thoroughly disastrous for brain repair is now known to produce some positive effects on stem/progenitor cell recruitment via the regulation of growth factor signaling and the secretion of a number of chemoattractant cytokines. This knowledge is crucial for the development of new therapeutic strategies. One of these strategies could consist in increasing the mobilization of endogenous progenitor cells that could replace lost cells and improve functional recovery.”

The April 2011 publication Adult Neural Stem Cells: Response to Stroke Injury and Potential for Therapeutic Applications reports “The plasticity of neural stem/progenitor cells allows a variety of different responses to many environmental cues. In the past decade, significant research has gone into understanding the regulation of neural stem/progenitor cell properties, because of their promise for cell replacement therapies in adult neurological diseases. Both endogenous and grafted neural stem/progenitor cells are known to have the ability to migrate long distances to lesioned sites after brain injury and differentiate into new neurons. Several chemokines and growth factors, including stromal cell-derived factor-1 and vascular endothelial growth factor, have been shown to stimulate the proliferation, differentiation, and migration of neural stem/progenitor cells, and investigators have now begun to identify the critical downstream effectors and signaling mechanisms that regulate these processes. Both our own lab and others have shown that the extracellular matrix and matrix remodeling factors play a critical role in directing cell differentiation and migration of adult neural stem/progenitor cells within injured sites. Identification of these and other molecular pathways involved in stem cell homing into ischemic areas is vital for the development of new treatments. To ensure the best functional recovery, regenerative therapy may require the application of a combination approach that includes cell replacement, trophic support, and neural protection.”

With aging there is normally a decline in the volume of the hippocampus along with a decline in memory and brain processing capability.  However, such declines appear not to be universal and may be averted.

The 2010 publication Involvement of BDNF in age-dependent alterations in the hippocampus reports.”It is known since a long time that the hippocampus is sensitive to aging. Thus, there is a reduction in the hippocampal volume during aging. This age-related volume reduction is paralleled by behavioral and functional deficits in hippocampus-dependent learning and memory tasks. This age-related volume reduction of the hippocampus is not a consequence of an age-related loss of hippocampal neurons. The morphological changes associated with aging include reductions in the branching pattern of dendrites, as well as reductions in spine densities, reductions in the densities of fibers projecting into the hippocampus as well as declines in the rate of neurogenesis.”

Brain-derived neurotrophic factor (BDNF) is a factor critically involved in the regulation of age-related processes in the hippocampus including loss of hippocampal volume.

The previously-mentioned publication reports “In this review it is hypothesized that brain-derived neurotrophic factor (BDNF) is a factor critically involved in the regulation of age-related processes in the hippocampus. Moreover, evidences suggest that disturbances in the BDNF-system also affect hippocampal dysfunctions, as e.g. seen in major depression or in Alzheimer disease.” For background on BDNF see my March 2010 blog entry BDNF gene – personality, mental balance, dementia, aging and epigenomic imprinting.  That blog entry discusses BDNF in relationship to dementia, mental balance, aging, mental exercise and epigenetics.

The 2010 publication   Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume relates “Hippocampal volume shrinks in late adulthood, but the neuromolecular factors that trigger hippocampal decay in aging humans remains a matter of speculation. In rodents, brain-derived neurotrophic factor (BDNF) promotes the growth and proliferation of cells in the hippocampus and is important in long-term potentiation and memory formation. In humans, circulating levels of BDNF decline with advancing age, and a genetic polymorphism for BDNF has been related to gray matter volume loss in old age. In this study, we tested whether age-related reductions in serum levels of BDNF would be related to shrinkage of the hippocampus and memory deficits in older adults. Hippocampal volume was acquired by automated segmentation of magnetic resonance images in 142 older adults without dementia. The caudate nucleus was also segmented and examined in relation to levels of serum BDNF. Spatial memory was tested using a paradigm in which memory load was parametrically increased. We found that increasing age was associated with smaller hippocampal volumes, reduced levels of serum BDNF, and poorer memory performance. Lower levels of BDNF were associated with smaller hippocampi and poorer memory, even when controlling for the variation related to age. In an exploratory mediation analysis, hippocampal volume mediated the age-related decline in spatial memory and BDNF mediated the age-related decline in hippocampal volume. Caudate nucleus volume was unrelated to BDNF levels or spatial memory performance. Our results identify serum BDNF as a significant factor related to hippocampal shrinkage and memory decline in late adulthood.”

“Changes in the concentration of brain-derived neurotrophic factor (BDNF) might be contributing to shrinkage of the hippocampus in late adulthood. BDNF, a molecule that is highly concentrated in the hippocampus (Murer et al., 2001; Phillips et al., 1990; Wetmore et al., 1990), is important in synaptic plasticity (Figurov et al., 1996; Kang & Schuman, 1995; Pang et al., 2004; Stoop & Poo, 1996; Tanaka et al., 2008) and is thought to contribute to neurogenesis in the dentate gyrus (Benraiss et al., 2001; Pencea et al., 2001; Takahashi et al., 1999), but its concentration declines in late adulthood (Lommatzsch et al., 2005; Ziegenhorn et al., 2007, however see Lapchak et al., 1993). Smaller hippocampal volumes predict more rapid conversion to dementia (Grundman et al., 2002) and poorer memory function (Erickson et al., 2009) (ref).”

Polymorphisms in the BDNF gene can be associated with mental disorders and such changes can also affect hippocampus volume

The above-mentioned blog entry discusses how the Val66Met polymorphism of the BDNF gene can affect mental states and dementia. 

“In humans, a single nucleotide polymorphism in the BDNF gene affects the regulated secretion of BDNF in the hippocampus (Egan et al., 2003) and has been related to lower serum levels of BDNF (Ozan et al., 2010) and smaller hippocampal volumes (Bueller et al., 2006; Pezawas et al., 2004; Szeszko et al., 2005)—RESULTS Hippocampal, but not caudate nucleus volume, declines with increasing age.  Consistent with prior research (e.g. Raz et al., 2005), hippocampal volume declined with advancing age after adjusting for total intracranial volume and sex. — Spatial memory performance declines with increasing age — Larger hippocampal volumes were positively associated with spatial memory performance — BDNF is positively related to spatial memory performance — we found that increasing age was associated with reduced levels of BDNF, and reduced levels of BDNF were related to both decline in hippocampal volume and elevated memory deficits.  — Interestingly, the mediation results of the hippocampus on age-related memory decline were relatively specific to the left hippocampus, and not to the right. Other studies have reported asymmetries in the volume and function of the left and right hippocampus (Erickson et al., 2009) and suggest that the left and right hemispheres might play different, but complementary roles, in memory tasks that emphasize speed. Our results suggest that the left hippocampus is related to measures of speed for all memory set sizes, and the right hippocampus only for the 3-item condition(ref).”

Exercise causes upregulated expression of BDNF leading to increase in hippocampus size and memory improvement

The 2011 publication Exercise training increases size of hippocampus and improves memory reports “The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.”  The effect is not a large one but is still significant.”

One mechanism that may be involved in increasing brain volume through exercise may be the increased expression of BDNF brought about by exercise.  The positive effect of exercise on BDNF expression has been noted for some time, for example in the 2002 publication Voluntary Exercise Induces a BDNF-Mediated Mechanism That Promotes Neuroplasticity.  Another is Endurance training enhances BDNF release from the human brain.

In the recent blog entry PQQ – activator of PGC-1alpha, SIRT3 and mitochondrial biogenesis I discussed how the supplement substance PQQ encourages mitochondrial biogenesis emulating exercise in that regard, and is neuroprotective. PQQ works via mitochondria by upregulating expression of the PGC-1alpha gene and expression of the SIRT3 gene.  I looked hard at the literature to see what I could find out about interaction of the BDNF and PGC-1alpha/SIRT3 exercise-related pathways.  I discovered little, however, and it appears that the pathways probably function independently but possibly synergistically.

The blog post BDNF gene – personality, mental balance, dementia, aging and epigenomic imprinting point out how mental exercise also stimulates expression of BDNF and longevity.  See too the blog posts Mental exercise and dementia in the news again and Brain fitness, Google and comprehending longevity .

Cognitive and memory decline with age is not inevitable and can be influenced by many factors including diet and exercise.

Maintaining neuronal and cognitive plasticity is important for averting age-related memory decline and cognitive aging. 

The November 2010 publication Neuronal and Cognitive Plasticity: A Neurocognitive Framework for Ameliorating Cognitive Aging relates: “Neuronal plasticity (e.g., neurogenesis, synaptogenesis, cortical re-organization) refers to neuron-level changes that can be stimulated by experience. Cognitive plasticity (e.g., increased dependence on executive function) refers to adaptive changes in patterns of cognition related to brain activity. We hypothesize that successful cognitive aging requires interactions between these two forms of plasticity. Mechanisms of neural plasticity underpin cognitive plasticity and in turn, neural plasticity is stimulated by cognitive plasticity. We examine support for this hypothesis by considering evidence that neural plasticity is stimulated by learning and novelty and enhanced by both dietary manipulations (low-fat, dietary restriction) and aerobic exercise. We also examine evidence that cognitive plasticity is affected by education and training. — Across a range of species – rats, monkeys, and humans – a sizeable subset of older individuals do not succumb to cognitive or brain decline (Willis and Schaie, 1986; Rapp and Amaral, 1991; Gallagher et al., 1993; Lee et al., 1994; Glisky et al., 2001). Moreover, even in old age the brain remains capable of plasticity – ability to change neurons and networks in response to experience (Kleim et al., 2003). The apparent persistence of plasticity late in life may provide some protection against age-related cognitive decline.”

The relationship between age-related brain shrinkage and cognitive capability is not clear

Continuing from the same publication: “The neural substrate of cognitive aging is not understood. Although cortical shrinkage occurs with age, such shrinkage is unrelated to cognitive change. Several research groups have attempted to relate regional cortical shrinkage to longitudinal cognitive change and found either an inverse relation or no relation (Rodrigue and Raz, 2004; Van Petten, 2004; Van Petten et al., 2004). Looking longitudinally over 5 years, shrinkage in neither hippocampus nor prefrontal cortex was related to cognitive change over the same period. Only shrinkage in entorhinal cortex, known to be the initial site of pathology of AD, was related to memory change (Rodrigue and Raz, 2004). Similarly, neuron loss in aging is minimal. Although for many years, age-related neuron loss was reported, the use of newer, un-biased, stereological techniques for counting neurons revealed no significant neuron loss in old age (reviewed in (Morrison and Hof, 1997). Although cross-sectional studies show near linear decline in many cognitive functions from young to old adulthood (Park et al., 2002), white matter actually increases over the same age range (Bartzokis, 2004). Synapse loss occurs only late in life after age 65 or so (reviewed in Masliah et al., 2006) and is reversible (reviewed in Greenwood, 2007). Effects of aging on biophysical properties of neurons are selective and subtle, seen only in specific brain regions and cell types (Burke and Barnes, 2006). Dopamine neurotransmission has been found to influence working memory performance, in a way that varies with age but also varies with cognitive performance regardless of age (Volkow et al., 1998; Backman et al., 2000). Thus, the substrate of cognitive aging is not known. One source of the difficulty in relating brain structure to cognitive change in old age may be the brain’s ability to adapt. In light of evidence that plastic changes leading to improved function after training can occur even following stroke (Taub et al., 2002; Ro et al., 2006), plastic changes may be ongoing, even in the face of cortical shrinkage and white matter damage. As reviewed below, there is evidence for such adaptation in old age in the heightened activation of cortical regions supporting executive resources, claimed to occur as compensation (Grady, 1996; Grady et al., 2005; Wingfield and Grossman, 2006).”

Exercise enhances neurogenesis and synaptic plasticity

Continuing: “ Animal work has consistently shown that physical exercise increases proliferation and survival of new neurons in the dentate gyrus of the hippocampus of adults (Gould et al., 1999; van Praag et al., 1999; Lou et al., 2008; Naylor et al., 2008). Rodents given access to a running wheel typically voluntarily run as much as 3–8 km per night and this is associated with a doubling or tripling of the number of newborn cells in the subventricular zone of the dentate gyrus where neurogenesis occurs. Voluntary wheel running over long periods of time is also associated with an increase in survival of later-stage progenitor cells and newly-formed (early post-mitotic) neurons in mouse dentate gyrus (Kronenberg et al., 2006). After experimental stroke, voluntary running enhanced progenitor cell survival in dentate gyrus in mice (Luo et al., 2007). This effect may extend beyond the hippocampus, as running rats also showed significantly higher number of cholinergic neurons in the diagonal band of Broca (Ang et al., 2003). — Some of the benefits of exercise on learning may be attributable to its effects on mechanisms of synaptic plasticity. LTP, which is a durable increase in the strength of a synapse after being repeatedly stimulated, appears to be the basis for memory formation, in that it can be induced by learning alone (Whitlock et al., 2006). In the dentate gyrus of the hippocampus, benefits of exercise have been observed on both neurogenesis (Pereira et al., 2007) and LTP (Farmer et al., 2004). Finally, exercise also alters the length and complexity of dendrites and of the density of the spines found on dendrites (Eadie et al., 2005). These exercise-induced dendritic changes can improve the efficiency of communication between neurons.”

The discussion in the publication goes on to point out that factors favoring brain plasticity include many of the “usual suspect” healthy lifestyle and dietary patterns and supplements that I have discussed in multiple past blog entries including confronting daunting mental challenges, avoidance of dietary fat, adherence to a Mediterranean-type diet , and taking omega-3 fatty acids and  resveratrol.

Curcumin is also a powerful promoter of neurogenesis in the hippocampus

The August 2010 blog entry Neurogenesis, curcumin and longevity is specifically concerned with the impact of the dietary supplement curcumin on neurogenesis in the hippocampus and the impact of curcumin neural plasticity.

All behavioral experience as well as lifestyle patterns are reflected in epigenetic records which impact neuron and synapse formation in the hippocampus

I have written frequently about the all-pervasive effects of epigenetic records in the aging process.  A specific discussion of such an effect is provided in the 2010 publication Synaptogenesis in adult-generated hippocampal granule cells is affected by behavioral experiences.  “Adult-generated hippocampal immature neurons play a functional role after integration in functional circuits. Previously, we found that hippocampus-dependent learning in Morris water maze affects survival of immature neurons, even before they are synaptically contacted. Beside learning, this task heavily engages animals in physical activity in form of swimming; physical activity enhances hippocampal neurogenesis. In this article, the effects of training in Morris water maze apparatus on the synapse formation onto new neurons in hippocampus dentate gyrus and on neuronal maturation were investigated in adult rats. — The main result we found was the anticipated appearance of GABAergic synapses at 6 days in learner, cued and swimmer rats, supported also by immunohistochemical result. Swimmer rats showed the highest percentage of GFP-positive neurons with glutamatergic response at 10 and 12 days postmitosis. Moreover, primary dendrites were more numerous at 7 days in learner, cued and swimmer rats and swimmer rats showed the greatest dendritic tree complexity at 10 days. Finally, voltage-dependent Ca(2+) current was found in a larger number of newborn neurons at 7 days postinfusion in learner, cued and swimmer rats. In conclusion, experiences involving physical activity contextualized in an exploring behavior affect synaptogenesis in adult-generated cells and their early stages of maturation.”

The 2010 publication An epigenetic hypothesis of aging-related cognitive dysfunction suggests “a new hypothesis for the role of epigenetic mechanisms in aging-related disruptions of synaptic plasticity and memory. Epigenetics refers to a set of potentially self-perpetuating, covalent modifications of DNA and post-translational modifications of nuclear proteins that produce lasting alterations in chromatin structure. These mechanisms, in turn, result in alterations in specific patterns of gene expression. Aging-related memory decline is manifest prominently in declarative/episodic memory and working memory, memory modalities anatomically based largely in the hippocampus and prefrontal cortex, respectively. The neurobiological underpinnings of age-related memory deficits include aberrant changes in gene transcription that ultimately affect the ability of the aged brain to be “plastic”. The molecular mechanisms underlying these changes in gene transcription are not currently known, but recent work points toward a potential novel mechanism, dysregulation of epigenetic mechanisms. This has led us to hypothesize that dysregulation of epigenetic control mechanisms and aberrant epigenetic “marks” drive aging-related cognitive dysfunction.”  The article focuses on “reviewing current knowledge concerning epigenetic molecular mechanisms, as well as recent results suggesting disruption of plasticity and memory formation during aging.”

Wrapping it up

·        There are several important changes in human brains that typically start in middle age and that accelerate with advancing age: hippocampus size decreases, BDNF expression decreases, there is significant shrinkage of gray matter; there is a decrease in neurogenesis and often but not always decrease in cognitive capability and loss of memory.

·        Shrinking of the hippocampus, the prefrontal cortex, entorhinal cortex, and caudate nucleus in late adulthood are thought to contribute to the patterns of cognitive and memory decline often observed in older adults.

·         Age-related loss of neurogenesis is thought to be a main factor leading to age-related decline.  Neurogenesis in the brain is a tightly controlled lifelong process.  It primarily takes place in neurogenic niches in parts of the hippocampus.  New neurons migrate to their destination locations. 

·        Disorders in BDNF gene expression are implicated in many aberrant mental conditions and Alzheimer’s disease.  BDNF expression decreases with age and age-related loss in BDNF expression is thought to lead to hippocampal shrinking with age.

·        Maintaining neuronal and cognitive plasticity is important for averting age-related memory decline and cognitive aging.

·        Cognitive and memory decline with age is not inevitable and can be influenced by many factors.   Neurogenesis, BDNF expression and synaptic plasticity are highly dynamic processes in healthy individuals.  They can be upregulated with physical and mental exercise, good lifestyle patterns, via good diet and via taking certain supplements including resveratrol, curcumin and omega3 fatty acids.

·        Epigenetic regulation of brain aging is a new topic that I expect will attract significant attention as time progresses, revealing the behavior-driven gene-activation mechanisms that affect brain aging and the mechanisms that inhibit such aging. 

·        Besides the materials discussed here, a search of the index of this blog will reveal many additional articles on the key topics discussed here as well as many related topics such as Alzheimer’s disease.

I intend to keep researching and writing interesting new entries for this blog.  And I would also like to see a greater frequency of blog entries to keep up with what is going on related to aging sciences.  To accomplish this and to fulfill the Mission implied by the new blog name Aging Sciences, I need help. 

Back in February in the blog entry The evolution of my perspective as a longevity scientist, I wrote “I am not sure how much longer I can keep up with the central research developments relevant to longevity.  The pace of research is increasing and many of the key discoveries are increasingly technical.  I have had to be more selective in picking topics for blog entries.  And I am struggling harder and harder to understand what is going on in the areas of some of my blog entries(ref).”  In a comment the reader Peter had to say “Vince, you mention the difficulty in keeping up with the research which pertains to each potential cause of aging. I wonder if you have given thought to farming some of this out? For example, if you had a small team (2 to 6) of like-minded people who each agreed to take on one or two theories/pathways to stay on top of, and to distill the information down into clearly written living summaries (complete with sourcing) it might go along ways to allowing you to have the time to integrate all of this into a meaning full whole and step back enough to see patterns and interconnection among the theories/pathways.”

I think Peter’s suggestion is excellent and I would like to proceed with it.  So, I am looking for a few Associate Researchers/Writers to join me.  I am initially looking for people who can cover relatively broad swaths of the longevity sciences in depth as I have been doing.  Later, it may make sense to add more researchers/writers focusing on specialized areas.  In such a case, the initial Associates could possibly graduate to becoming Area Editors.  So I am herewith putting out a “casting call.”

CASTING CALL FOR ASSOCIATES

If you satisfy the following, please communicate with me by e-mail:

   ·        You have a passionate interest in the longevity sciences or in an applied area related to longevity, perhaps with a focus in a certain key area,

  ·        You are good at perusing the scientific literature to see what is going on,

  ·        You can express yourself well in writing and would like that writing to have targeted exposure that generates feedback,

  ·        You have sufficient training, background and patience to scan key areas of the emerging literature, identify important new trends, and generate blog entries with the sophistication and degree of literature documentation typically found in this blog.  A number of  readers have commented that this blog is the best source of scientific information related to aging on the web.  I want to keep it that way,

  ·        You are aligned with the Mission of this blog and willing to respect the blog guidelines outlined here.  The Mission of the blog is to present clearly information on key current research developments pertaining to aging and information on related technological and social topics.  Secondarily, it is to share informed opinions on the same topic.  The target audience includes professionals and students in the aging science community, health and geriatric practitioners, and informed individuals with a substantial interest in aging and aging sciences. 

  ·        You would like to get your signed writings out to a growing International community which I estimate currently to be more than 15,000 regular readers.  Currently, about 2,000 different readers visit the blog every day and new registrations from all over the world keep coming in every day.

  ·        You are willing to research and write at least one blog entry a month.  Documented mini-reviews of key topics are particularly welcome. The history of previous blog entries illustrates consider acceptable topics and blog formats, the degree of citation documentation, and the quality of the writing I will be looking for. 

  ·        You are willing to follow the general guidelines of this blog such as no commercial product promotions, no giving of medical advice and staying broadly “on topic” with respect to longevity.  While individual blog entries can be concerned with specific theories of aging or anti-aging interventions, the blog itself is inclusive of a wide variety of viewpoints provided that they are informed and anchored in respectable research.  Opinions, when offered, will be identified as such.  And I will also entertain occasional humor pieces,

  ·        You are willing to work now for the same compensation I am getting – zero pay but significant acknowledgement and opportunity to learn,

  ·        You are willing to have me review and possibly lightly edit your blog entries before they are published on the blog.  And I will reserve the right to not publish any writings if I feel they don’t meet quality or other standards of the blog.   

 My e-mail is vegiuliano@comcast.net.  Please use the e-mail heading BLOG WRITER so I can easily sort your message out from junk.  Tell me about yourself, your background, what you know/don’t know, your academic and work status, any institutional affiliation you may have or had, why you want to contribute and what you have to offer.  Also please point me to online examples of your relevant writings or attach same to your e-mails.  Finally, you might wish to identify the subject of any initial blog entries you might want to write. 

If I invite you to join me as an Associate, I will do an editorial review of your blog entries before they go online and everything you write will be attributable to your authorship.

Please do not let your age or academic or institutional status be seen as a barrier here if you have what it takes to do the job.  Whether you are a vital oldster like me or a young graduate student, this could be an opportunity to get yourself out to a big audience of readers and make a difference.