Yuan et al. have identified another anti-cancer effect of the “longevity” protein SIRT1. By speeding the destruction of the tumor promoter c-Myc, SIRT1 curbs cell division. The study will be published online April 13 (www.jcb.org) and will appear in the April 20 print issue of the Journal of Cell Biology.

The yeast and nematode equivalents of SIRT1 are fountains of youth that stretch lifespan. Whether SIRT1 slows aging in mammals isn’t certain, but it’s beneficial in other ways. The protein tunes up metabolism, reducing blood levels of glucose and insulin, and might forestall neurodegenerative illnesses such as Alzheimer’s disease and ALS. Given its pro-life credentials, you might expect SIRT1 to inhibit cancer. And several studies suggest that it does. But other work indicates that the protein aids tumors. For example, SIRT1 chops off acetyl groups, which can inactivate the tumor suppressor p53.

Yuan et al. determined SIRT1’s effect on the transcription factor c-Myc, whose expression surges in many breast, colon, and liver cancers. The two proteins are tangled in a regulatory loop, the team found. c-Myc latched onto SIRT1’s promoter, spurring cells to manufacture more SIRT1. In turn, SIRT1 detached acetyl groups from c-Myc, hastening its breakdown. To test SIRT1’s effects on tumor growth, the researchers implanted cancerous cells expressing c-Myc into nude mice that lack immune defenses. Boosting production of SIRT1 blocked tumor formation.

How deacetylation of c-Myc sparks its destruction is still a mystery. The researchers say that the results don’t necessarily conflict with studies suggesting that SIRT1 is pro-tumor. Whether SIRT1 promotes or prevents cancer probably depends on the situation.

Reported in the Journal of Clinical Investigation, THC was shown to induce human glioma (brain cancer) cell death through a process known as autophagy, and did so by activating a particular stress response in the cells.

DHA, in an article soon to be published in Cell Division, was shown to reduce the size of tumours and enhance the positive effects of the chemotherapy drug Cisplatin. In particular, DHA strongly mitigated the toxic effect of Cisplatin on the kidneys while simultaneously increasing its effectiveness against cancer cells.

Of course, both substances – especially cannabinoids – have been attributed with anti-cancer properties for quite a while, but it’s always good to obtain further insight into the mechanisms by which these effects are exerted, particularly with cannabis, which is often difficult to research on account of its illegality in many parts of the world.

Anyhow, I’m cheered: at the rate I’m going, I don’t think I’ll ever get brain cancer

L-carnitine is a naturally occurring compound which is primarily located in mitochondria and possesses potential protective effects against many mitochondrial toxic agents. It is derived from two sources: endogenous synthesis, in the liver and kidney, and from exogenous dietary sources such as red meat and dairy products. L-carnitine is an essential cofactor for the translocation of long chain fatty acids from the cytoplasmic compartment into mitochondria, where beta-oxidation enzymes are located for ATP production.

To test their hypothesis, the researchers studied a rat model of hepatocarcinogenesis under conditions of carnitine deficiency and supplementation.

L-carnitine supplementation resulted in a complete reversal of the cancer-related changes in the rats’ livers.

Given these promising results, they intend to conduct further investigations into the mechanisms behind carnitine’s anti liver cancer effect.

Carnitine supplementation, particularly in the form of acetyl-L-carnitine (ALCAR), which is cheaply available from a number of suppliers, has a reasonably long history of conferring health and longevity benefits. In my opinion, it’s one of the cornerstones of an effective supplementation regime, particularly in combination with alpha lipoic acid (ALA).

Which is to say, you’re less likely to get melanoma if you spend all day out in the sun smoking cigarettes. Of course, your chances of getting lung cancer will be greatly enhanced, but whatever.

It appeared to be the degree of ’skin aging’ – the loss of elastin and collagen that makes skin look old and saggy (a process that occurs sooner in smokers) – that conferred resistance to melanoma.

I don’t really know what to make of this! Personally, I’d avoid the cigarettes but continue with my fairly lax approach to UV protection. What do you think?

Here’s the abstract:

Skin aging from ultraviolet irradiance and smoking reduces risk of melanoma: epidemiological evidence.

Anticancer Res. 2008 Nov-Dec;28(6B):4003-8. PMID: 1919266

Grant WB.
Sunlight, Nutrition, and Health Research Center (SUNARC), P.O. Box 641603, San Francisco, CA 94164-1603, USA. wbgrant@infionline.net

Long-term smoking appears to be inversely correlated with development of melanoma. Chronic ultraviolet (UV) irradiance also reduces and/or delays the development of melanoma. Thus, a common process is indicated. To examine the link between smoking and melanoma, articles reporting the relation between incidence of lung cancer and melanoma for individuals were sought. A very strong inverse correlation (r = -0.96) was found between the standardized incidence ratios for lung cancer and melanoma, passing through the value of 1 for each with a slope of -0.74. Smoking increases skin aging or elastosis in a manner similar to that of UV irradiance. Development of elastosis seems to explain why long-term smoking and chronic UV irradiance reduce the risk of melanoma. Further work is required to elucidate the mechanism whereby elastosis retards and reduces the development of melanoma.

Quercetin is a polyphenol compound found in many plant based foods, namely onions, peppers, tomatoes, and wine. Personally, I take it in supplement form.

The press release is available here, and I’ll just summarize the facts of the somewhat long-winded press release for the sake of expediency:

• Quercetin had been shown previously to reduce colon cancer; this research explains why
• Amounts used in study are realistic for diet-only amounts (no need to supplement)
• Quercetin reduces the number of ‘aberrant crypts’ – proto-colonic lesions that eventually develop into colon cancer
• Quercetin appeared to decrease cell proliferation and increase apoptosis (programed cell death of old or damaged cells) in the colon
• Quercetin appeared to reduce the levels of Cox-1 and Cox-2, inflammatory factors thought to be either a cause or effect of colon and other cancers

Okay, I admit that was pretty uninspiring, but that was the extent of the info given in the release.

The take home message is: Eat healthily; consider supplementing with quercetin.

Dr. Dan Peer of the Department of Cell Research and Immunology claims that Prozac works by blocking resistance to the anti-cancer drug. Specifically, it prevents the drug from leaving the interior of the cancer cell and poisoning the healthy, non-cancerous cells that surround it.

Unfortunately for the researchers, but fortunately for everyone else, is the fact that this therapy can’t be commercialized – any doctor can prescribe Prozac.

Dr. Peer and his colleagues will be conducting further research into Prozac’s anti-cancer capacities, to see if it enhances the effects of other cancer treatment modalities.

Soon, your cancer treatment may well just come packaged with a dose of mental quietude in a pill.

This is good news for lovers of ginger, such as myself. Cheers!

Ginger extract (Zingiber officinale) has anti-cancer and anti-inflammatory effects on ethionine-induced hepatoma rats.

Clinics. 2008 Dec;63(6):807-13. PMID: 19061005

Habib SH, Makpol S, Hamid NA, Das S, Ngah WZ, Yusof YA.

Department of Biochemistry, Medical Centre, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur.

OBJECTIVE: To evaluate the effect of ginger extract on the expression of NFkappaB and TNF-alpha in liver cancer-induced rats. METHODS: Male Wistar rats were randomly divided into 5 groups based on diet: i) control (given normal rat chow), ii) olive oil, iii) ginger extract (100mg/kg body weight), iv) choline-deficient diet + 0.1% ethionine to induce liver cancer and v) choline-deficient diet + ginger extract (100mg/kg body weight). Tissue samples obtained at eight weeks were fixed with formalin and embedded in paraffin wax, followed by immunohistochemistry staining for NFkappaB and TNF-alpha. RESULTS: The expression of NFkappaB was detected in the choline-deficient diet group, with 88.3 +/- 1.83% of samples showing positive staining, while in the choline-deficient diet supplemented with ginger group, the expression of NFkappaB was significantly reduced, to 32.35 +/- 1.34% (p<0.05). In the choline-deficient diet group, 83.3 +/- 4.52% of samples showed positive staining of TNF-alpha, which was significantly reduced to 7.94 +/- 1.32% (p<0.05) when treated with ginger. There was a significant correlation demonstrated between NFkappaB and TNF-alpha in the choline-deficient diet group but not in the choline-deficient diet treated with ginger extract group. CONCLUSION: In conclusion, ginger extract significantly reduced the elevated expression of NFkappaB and TNF-alpha in rats with liver cancer. Ginger may act as an anti-cancer and anti-inflammatory agent by inactivating NFkappaB through the suppression of the pro-inflammatory TNF-alpha.

When cells experience genetic damage, for example as a result of radiation or oxidative stress, if that damage is severe enough, they enter a state of senescence. They no longer divide because to do so would risk abnormal growth and malignancy due to their heavily corrupted genome.

However, while this response exists supposedly to suppress cancer, these senescent cells develop a condition known as SASP – senescence-associated secretory phenotype, which means they secrete factors into the cellular microenvironment that might contribute to age-related pathologies by promoting inflammation and malignancy.

The exact composition of these secretions is not yet known, remaining to be elucidated in further study.

This is thought to be an example of ‘antagonistic pleiotropy‘ – an evolutionary theory suggesting that if one gene controls multiple outcomes, some of which are good in early life and favor reproduction but are bad in later life, they will nevertheless be selected for. In primordial natural environments, hazards abound and old individuals are rare, so their is little pressure from the environment for organisms to evolve such that old individuals are favored. Similarly in humans, given that our reproductivity ends in mid life, there is no evolutionary advantage gained from living to a ripe old age.

As we age, the number of senescent cells increases, and high concentrations of these cells are often found at the sites of age-related pathologies such as osteoarthritis and atherosclerosis, both of which are thought to be caused, or at least facilitated, by chronic inflammation.

In fact, the tumor suppressor gene p53, if chronically active, promotes cellular senescence and therefore also accelerates aging.

Hence, the more cancer-resistant you are, the sooner you are likely to experience the effects of age.

Ultimately, what this might mean for anti-aging is that future study should focus on methods to remove senescent cells from the body, or at least reduce the likelihood of cells becoming senescent in the first place. It’s not clear from the study whether cells that have become senescent as a result of telomere shortening also exhibit SASP, but if so this might explain the seemingly sudden acceleration of the aging process in later life.

Also, it would be excellent if terminally damaged cells committed apoptosis rather than senesced, and hopefully further research will look into how the apoptotic pathway could be favored. Also, methods to differentiate and selectively kill senescent cells or block the expression of SASP would be highly appreciated!

Reference: Jean-Philippe Coppé et al. Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor. PLoS Biology. 2 December 2008

The article is reasonably technical, but I’ll summarize the results here:

Green tea polyphenol (GTP) supplementation in mice prevents photocarcinogenesis (i.e., skin cancer). I’ve not mentioned this before, so here’s a link to a review on the matter.

Salient points from above-mentioned review:

Extensive in vitro and in vivo studies have been conducted to determine the anti-UV carcinogenic effects of green tea. It has been found that the oral administration of GTPs (a mixture of polyphenolic components isolated from green tea) in the drinking water of mice results in significant protection against UV-induced skin carcinogenesis in terms of tumor incidence, tumor multiplicity and tumor size, compared to those mice that were not given GTPs in their drinking water.

The mice that were given crude water extracts of green tea as a sole source of drinking water developed a lesser number of tumors compared to those mice that were not given water extracts of green tea. The administration of GTPs in drinking water or the topical application of EGCG also induced partial regression or inhibition of the tumor growth of established skin papillomas in mice.

The researchers in this case showed that GTP supplementation in mice reduced the levels of inflammation markers cyclooxygenase-2, prostaglandin E2, proliferating cell nuclear antigen, and cyclin D1, and proinflammatory cytokines tumor necrosis factor-alpha, IL-6, and IL-1-beta. UVB-induced DNA damage was rapidly resolved in the GTP-supplemented mice compared with the wild type mice.

The major contribution of this study was that all these effects appear to be mediated through interleukin 12.

Personally, I have been supplementing with Now Foods EGCg Green Tea extract, available from bulknutrition.com. At 4 capsules per day, this is apparently equivalent to 12 cups of green tea. Hopefully this will keep me skin cancer free!

Traditionally, the anti-aging effects of telomerase have been poorly explored because of its unfortunate cancer-promoting activity. Consequently, the researchers genetically engineered cancer-resistant mice by up-regulating their expression of tumor suppressor proteins p53, p16, and p19ARF.

TElomerase Reverse Transcriptase (TERT, or just ‘telomerase’) was additionally overexpressed to observe the anti-aging effects of increasing its concentrations in the cell. It was found that TERT overexpression improved the fitness of epithelial barriers (particularly the skin and the intestine) and produced a systemic delay in aging, as well as an actual extension of the median life span.

Also, the genetically enhanced mice showed a better preservation of both the thickness of the epidermis and of the subcutaneous fat layer compared to the controls. What this means is, if they were humans, one of the main factors that is the cause of the appearance of old age, i.e. subcutaneous fat loss, would be somewhat reduced.

Interestingly, with regard to their lifespans: The mice that had their tumor suppression capabilities enhanced, but lacked TERT enhancement, saw no increase in lifespan. Those mice with both modifications saw a 26% increase in median lifespan. Of these mice, those that did not die of cancer (i.e., those that could be considered to have died of ‘old age’) experienced a 38% increase in median lifespan.

Translated into human terms, this would make living to an age of 110 years commonplace.

All in all, this is a very exciting study that suggests that if we can somehow eliminate the threat of cancer, steps towards markedly slowing the rate of aging are definitely in the pipeline. This is just one of the many fronts on which aging is being gradually defeated by the force of human ingenuity. I’m looking forward to the future developments of this research!

Some brief fundamentals:

What are telomeres?
Inside the nuclei of our cells, DNA doesn’t just sit there in a loose, tangled string. It is highly organized, with several orders of organization that become apparent as it is viewed at an increasing scale. At the smallest level, DNA is wrapped around a disc-shaped protein called a histone octamer. There are many of these histone complexes running along the DNA strand, giving it a ‘beads on a string’ appearance. These ‘beads’ are refered to as ‘nucleosomes’.

Nucleosomes then arrange themselves into fibrils, then the fibrils are super-coiled into chromatin fiber. The chromatin fiber forms loops or ‘domains’ ranging from 30,000-100,000 base pairs in length, which are eventually aggregated to form the highest order structure, the chromosome. It can be thought of as coils upon coils upon coils upon coils, and this is how such a long strand of DNA (around 3 metres in humans) can fit inside the nucleus of a cell.

At the end of each chromosome is where we find the telomere. Telomeres consist of short, repeating, TG-rich DNA sequences. Human telomeres have a variable number of repeats of the sequence 5′-TTAGGG-3′, which can extend for several kilobases.

What causes telomere shortening?
Functional telomeres are essential for continuous cellular proliferation; however, maintaining telomeres of adequate length is problematic for the cellular machinery. For a variety of complicated hypothetical reasons to do with the mechanics of DNA replication, each time the cell divides, the two resulting chromosomes have slightly shorter telomeres than the original.

The average rate of loss is estimated to be around 50-75 base pairs per telomere per cell division.

To compensate for this loss, we have the enzyme telomerase. Telomerase is a multisubunit RNA-containing complex related to viral RNA-dependent DNA polymerases (reverse transcriptases). It is the enzyme responsible for telomere synthesis and thus for maintaining the length of the telomere.

In adult cells, telomerase is inactive or only present at very low levels. It has been suggested that the purpose of this progressive erosion of the telomeres, coupled with the progressive inactivation of telomerase, is to place an upper limit on the number of times a cell can divide, so that cells whose proliferative schedule is corrupt – i.e., tumors – will be automatically limited to a set number of replications, limiting the potential for damage. Of course, cunning as they are, tumors often turn the production of telomerase back on, thereby immortalizing themselves.

Telomere shortening prevents cancer, but promotes aging
Because our cells have an upper limit placed on their proliferative capacity, at some point in time they lose their ability to replicate. As we grow older, the regenerative capacity of our cells deteriorates, and this is considered to be one of the main reasons that we age.

So, we’re faced with a dilemma: If we activate telomerase, we facilitate the unrestricted cellular division that is cancer; if we inactivate it, our life force is doomed to eventually grind to a sad, grey halt.

Fortunately for the mice in the above study, they were genetically engineered to have super tumor-resistant cells.

What are p53, p16, and p19ARF, and how do they prevent tumors?

p53 is a transcription factor that has the following important properties:

• It can activate DNA repair proteins when DNA has sustained damage.
• It can also hold the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.)
• It can initiate apoptosis, programmed cell death, if the DNA damage proves to be irreparable.

p16 is a gene that can produce a protein that can interact with and sequester MDM2, a protein responsible for the degradation of p53. So in essence, p16 stops p53 from being destroyed, maintaining adequate levels in the cell.

p19ARF is a mouse protein that also regulates MDM2’s ability to inhibit p53. The absence of the gene that encodes this protein (INK4a) leads to inappropriate cell survival and a higher incidence of cancer.

Reference: Telomerase Reverse Transcriptase Delays
Aging in Cancer-Resistant Mice. Cell 135, 609–622, November 14, 2008

Photo credit: lesliemiperry, Flickr