AGINGSCIENCES™ – Anti-Aging Firewalls™

Suppose there were a place in the world where there is a concentration of research laboratories busy working on antibiotics, cures for diseases, means for neutralizing environmental toxins and other molecular approaches that make for longevity.  Suppose further that these laboratories have been doing such work for a long time and have already discovered hundreds if not thousands of molecular-based longevity solutions – solutions unknown in our mainline science.  Suppose further that means for efficient manufacturing of these molecular solutions have also been worked out in these laboratories and that the solutions have already been tested and shown to work in various species.  Finally, suppose that there are literally billions of such laboratories concentrated in many places in the world. 

All this exists.  The laboratories are plants, insects and fauna.  The solution-discovery process is called evolution, rainforests are among the places where the biomolecular solution process takes place, and the laboratories have been at it for hundreds of millions of years.  This post is about disovering health and longevity solutions by studying such laboratories.

To begin, I point out a few facts about rainforests and that many of our important existing drugs are based on rainforest plants.  From Rainforest Facts” “Currently, 121 prescription drugs currently sold worldwide come from plant-derived sources. And while 25% of Western pharmaceuticals are derived from rainforest ingredients, less than 1% of these tropical trees and plants have been tested by scientists.” “More than half of the world’s estimated 10 million species of plants, animals and insects live in the tropical rainforests. One-fifth of the world’s fresh water is in the Amazon Basin.” ‘One hectare (2.47 acres) may contain over 750 types of trees and 1500 species of higher plants.”  “Nearly half of the world’s species of plants, animals and microorganisms will be destroyed or severely threatened over the next quarter century due to rainforest deforestation.”

Among the important existing drugs derived from rain forest plants are Neostigmine used for glaucoma, Quinine for treating malaria and inflammatory diseases, Cocaine-derived anesthetics, Turbocuarine-based muscle relaxants, Vincristine and Vinblastine used to treat pediatric leukemia and  Hogkin’s disease, and Cortisone is used for many purposes and is the active ingredient in birth control pills(ref).

The process of drug-discovery based on studying rainforest plants is a very different than the conventional drug-discovery approaches based on massive screening of compounds, improving on existing drugs or taking advantage of unique molecular pathways.  Conventional drug and biotech companies may be at a disadvantage for such rainforest discovery compared to new eco-discovery companies.  A place to start can be traditional cures used by indigenous people and known to shamans. 

Shaman Pharmaceuticals is a San Francisco company concerned with: Integrating Indigenous Knowledge, Tropical Medicinal Plants, Medicine, Modern Science and Reciprocity into a Novel Drug Discovery Approach.  “Shaman Pharmaceuticals, Inc. is a South San Francisco-based pharmaceutical company that focuses on isolating bioactive compounds from tropical plants that have a history of medicinal use. Shaman is working to promote the conservation of tropical forests and bridge the gap between the biomedical needs of both indigenous cultures and the rest of the global population. Eschewing the mass screening approach typically done by many pharmaceutical companies, Shaman has pioneered a novel approach to drug discovery, integrating traditional plant natural products chemistry, the science of ethnobotany, medicine, and medicinal chemistry while maintaining a commitment of reciprocity to the indigenous cultures.”  Shaman Pharmaceutical’s operations began in 1990. Utilizing the ethnobotanical/ethnomedical approach to collecting tropical medicinal plant species, Shaman has been successful in bringing two products into clinical trials within 24 months of that time. This focused approach  is currently being used in Shaman’s antidiabetic discovery program. Since the inception of the diabetes program two years ago, Shaman has discovered multiple new chemical leads from plant sources and, to date, patents have been filed on five of them. Each of these chemical leads is currently undergoing preclinical evaluation(ref).“

Another eco-discovery company is the Australian company Ecobiotics(ref), which works in rainforests in Australia. “The researchers at EcoBiotics take a more encompassing approach to exploring the Australian rainforests than do companies who search for new compounds in South America’s rainforests. EcoBiotics’ cofounders, Victoria Gordon, Ph.D., and Paul Reddell, Ph.D., are chemical and forest ecologists who live and work at the company’s headquarters near Cairns in the Daintree Rainforest of northeastern Australia. Their research team experiences firsthand the seasonal variation in plants, insect assaults, and invasions of microorganisms.  In contrast, researchers at other drug companies generally visit rainforests for a few weeks, collect plant materials, and take them back to laboratories to analyze them for new chemicals, according to Delco. The holistic approach at EcoBiotics “is like watching a movie instead of looking at snapshots,” he adds.”  “Plants evolve amazingly complex and dynamic chemical systems to survive. For example, when attacked by pathogenic microbes, plants use pattern recognition receptors to identify their assailants and produce specific antibiotics to defend themselves. “Attract-or-repel interactions create novel chemicals,” says Delco, as plants respond to injury, climate change, or invaders in a limited space(ref).” 

When dealing with rainforest plants, strange clues can lead to new drug discoveries.  “The observation that rainforest marsupials spit out seeds after eating the fruit of a certain plant led to the company’s lead compound, EBC-46. Scientists at EcoBiotics learned that the unpalatable seeds contain an inflammatory agent that made the animals’ tongues swell. They isolated the active ingredient, a diterpene ester, which belongs to a new class of chemicals.  EBC-46 shows anticancer properties against basal and squamous cell carcinomas, melanoma, and head and neck tumors, Delco reports. The active ingredient in EBC-46 is easily purified from a ubiquitous plant species that can be quickly grown on plantations. The company is developing a GMP process to insure commercial quantities of the drug for future investigations.  EBC-46 is a protein kinase C regulator that initiates apoptosis of tumor cells and causes a local inflammatory reaction that recruits the body’s neutrophils to attack the tumor. When injected into incurable soft tissue sarcoids, nasopharangeal cancers, and oral malignant melanomas in horses, dogs, and sheep, EBC-46 destroyed the tumors and healing was evident in about two weeks, Delco reports. The positive animal results “don’t guarantee that EBC-46 will work in people,” he adds, “but it’s promising.” EcoBiotics plans to file an investigational new drug application for EBC-46 within a year (ref).”

Several other rainforest drug discovery programs are reported from time to time in the news.  See, for example, Malaria: New drug lead from Madagascar’s rainforests.  Often, those interested in rainforest drug discovery are also interested in preservation of the rainforest eco-environments.  See Drug Discovery Program Helps Save Rainforests, Too.  For more background on ethnobotanical rainforest drug discovery you can see this and this and this references.

Returning to the first point in this post, rain forest biological entities have been doing anti-aging and health research hundreds of millions of years.  It can serve us well to learn about and take advantage of that research before the rainforests are decimated. 

Finally, a quick observation comparing research-in-the-laboratory and research-by-evolution.  This is about antibiotics against infectious pathogens like staph and strep, a battle that has been going on for 70 years now.  In the history of this period many highly effective antibiotic drugs have been rendered ineffective by the evolutionary emergence of drug-resistant pathogen microbe strains, the latest including ultra drug resistant strains of MRSA (methicillin-resistant Staphylococcus aureus).  On the one hand we have thousands of researchers wearing white coats in gleaming laboratories spending long hours and hundreds of millions or billions of dollars researching ways to develop new drugs that will kill the drug-resistant strains.  Linezolid, one of the few drugs effective aginst some but not all strains of MRSA, costs about $100 per pill.  Meanwhile, the microbes themselves are quietly doing research by evolving, finding ways to survive by altering their molecular mechanisms despite whatever new drugs we throw at them.  Who is winning?  Recent evidence says the evolving microbes are pulling ahead.

The update of my online treatise  Anti-Aging Firewalls – The Science And Technology Of Longevity mentioned in my last blog post has been completed and I expect to return to generating regular almost-daily blog entries tomorrow.  I believe the new theory of aging described there, the Stem Cell Supply Chain Breakdown theory, is likely to acquire increasing importance as time progresses.  This theory is based on insight gained in the process of doing my research over the last year and is, insofar as I know, original.

I am taking a break from new blog postings for a few days and focusing on an update of my Anti-Aging Firewalls treatise, particularly on a comprehensive re-formulation of the 14^th theory of aging.  Where the theory was Decline in Adult Stem Cell Differentiation, now I am creating a more comprehensive version to be called the Stem Cell Supply Chain Breakdown theory.  This is a major intellectual effort on my part and involves integrating new material with much information I have learned over the last year and scattered through many blog entries.  Drawing on an unfolding torrent of new research relating to stem cells, this theory offers the possibility of becoming actionable.  It could well point to incredible new anti-aging interventions.  If you want hints of what will be included check out these past blog postings: An emerging new view of aging – the stem cell supply chain, Rebooting cells and longevity, and Treating genetic diseases with corrected induced pluripotent stem cells.  One of the reasons why I am excited by this new theory of aging is that it is original.  Unlike the other 13 theories, to my knowledge this new theory cannot be found in the existing literature although pieces of it are scattered everywhere.  Expect me to finish this task and be back blogging soon.

In my May 2009 blog post Longevity genes, mTOR and lifespan, I discussed the mTOR signaling pathway in mammals, its role in diseases, the relationship of mTOR to mitochondrial activity and how inhibiting mTOR could conceivably be a strategy for extending longevity.  In my Anti-Aging Firewalls treatise I subsequently added ABERRANT mTOR SIGNALLING as one of six additional candidate theories of aging to be considered. Recently-reported research studies concerned with mTOR link up important subjects I have previously discussed in this blog.  I focus here on two such sets of links.

mTOR and the hypoxic response

The mTOR pathway is illustrated in this diagram and is seen to be fairly complex even though the diagram leaves some important links out.  For example, as illustrated in the diagram a condition of hypoxia activates TSC1/TSC2 which inhibits Rheb which, with AKT, would normally activate mTOR.  The net result is that hypoxia inhibits the expression of mTOR, providing a neat linkup of two of the additional candidate theories of aging: the ABERRANT mTOR SIGNALLING theory already mentioned and the THE HYPOXIC RESPONSE theory.  See the blog posting Another longevity-related biochemical pathway – the hypoxic response.  The hypoxic response is known to lengthen life in primitive organisms and inhibition of mTOR is also thought to be a possible life-extending intervention.  The diagram shows a key way in which the two theories weave together. 

For those of you interested in delving further, here are links to a few of the research publications linking up hypoxia and mTOR: Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex, Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling ,  and.  Hypoxia-induced energy stress inhibits the mTOR pathway by activating an AMPK/REDD1 signaling axis in head and neck squamous cell carcinoma. You may note that a lot of the current interest in controlling and limiting mTOR signaling is using this as an approach for suppressing tumors.

mTOR and the stem cell supply chain

In another important blog post An emerging new view of aging – the stem cell supply chain, I suggested a rather radical new view of aging and what can be done about it.  The essence if this view is: A.  the 210 different kinds of human cells can be separated into five categories: 1. pluripotent embryonic stem cells, 2. multipotent stem cells, 3. progenitor cells, 4. normal somatic cells and 5. senescent cells.  The list is in order of increasing cell-type specificity and decreasing potency to differentiate into other cell types.  Starting at conception and throughout life, all cells on this list except the senescent ones will selectively reproduce and differentiate into cells of types further down in the list.  Of course all the cells in an individual have the same genome but they acquire additional epigenomic markers as they differentiate.  I have referred to this process as the stem cell supply chain which must be kept in good working order if health is to be maintained.  B. Understanding aging requires understanding the stem cell supply chain – how and when stem and progenitor cells divide or differentiate and what makes them do that, and how this process can go wrong.  C.  Effective anti-aging interventions leading to extraordinary longevity will most likely require enhancing the operation of the stem cell supply chain.  It is no longer enough that anti-aging science is concerned with the life and death of cells.  It must also be concerned with the stem cell supply chain which provides the lifelong stream of cell renewal.

This April 2008 publication mTORC1 signaling governs hematopoietic stem cell quiescence relates mTOR signaling to the fate of an important pool of multipotent stem cells – hematopoietic stem cells (HCSs), the stem cells that give rise to the various blood cell types. “The stringent regulation of hematopoietic stem cell (HSC) quiescence versus cell cycle progression is essential for the preservation of a pool of long-term self-renewing cells and vital for sustaining an adequate supply of all blood lineages throughout life. Cell growth, the process that is mass increase, serves as a trigger for cell cycle progression and is regulated predominantly by mammalian target of rapamycin complex 1 (mTORC1) signaling. Emerging data from various mice models show deletion of several mTORC1 negative regulators, including PTEN, TSC1, PML and Fbxw7 result in similar HSC phenotypes characterized as HSC hyper-proliferation and subsequent exhaustion, and defective repopulating potential(ref).”  In other words, unless the negative regulators of mTORC1 are working well, the growth factors loosened by mTORC1 will cause the hematopoietic stem cells to reproduce like crazy exhausting the pool of these valuable cells – a major disruption in the stem cell supply chain.  

A second publication highlights the same point. “A balance between quiescence and proliferation of hematopoietic stem cells in interaction with the microenvironment is critical for sustaining long-term hematopoiesis and for protection against stress. — We demonstrated a pivotal role of two downstream effectors of the PI3K/Akt pathway, FoxO3a and mammalian target of rapamycin, as connectors in the SDF-1-/TGF–induced control of the cycling/quiescence switch and proposed a model integrating a dialogue between the two molecules in cell cycle progression(ref).”  Essentially the same point is made by a third study December 2008 publication mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization.  “TSC1 exists in a complex with TSC2 and functions primarily as a key negative regulator of mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis — Using hematopoietic stem cells (HSCs) as a model system, we demonstrate that somatic deletion of TSC1 produces striking stem cell and derivative effector cell phenotypes characterized by increased HSC cell cycling, mobilization, marked progressive depletion, defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. On the mechanistic level, we further establish that TSC1 regulation of HSC quiescence and long-term repopulating potential and hematopoietic lineage development is mediated through mTORC1 signaling(ref).”

Effective mTORC1 negative regulation is essential for keeping the stem cell supply chain working well, at least insofar as hematopoietic stem cells are concerned.

There is a lot more that can be said about the subjects of this post and I expect I will cover additional key points as time progresses.  For example, the AKT and AMPK pathways are interesting and relate to matters discussed both in my treatise and in this blog as well as to mTOR signaling.   Perhaps I will take on one of these at some point.

In a July blog post Warding off Alzheimer’s Disease and things in my diet, I talked about My usual breakfast: a sugar-free bran cereal with blueberries, walnuts and a sliced half-banana.  I cited research on the health benefits of the walnuts.  But what about the blueberries, the cupful or so I consume each morning?  It is common knowledge that they have strong antioxidant properties and “are good for you.” But what is known about their actual health benefits?  Actually, a great deal if animal models are to be trusted.  I reviewed some recent research on this subject and share the results here, mostly by listing quotes from the publications cited. I end each item with a simple summary of my own which is italicized.

·        Dietary blueberry attenuates whole-body insulin resistance in high fat-fed mice by reducing adipocyte death and its inflammatory sequelae, a new study, August 2009. “Salutary effects of BB on adipocyte physiology and ATMPhi gene expression may reflect the ability of BB anthocyanins to alter mitogen-activated protein kinase and nuclear factor-kappaB stress signaling pathways, which regulate cell fate and inflammatory genes. These results suggest that cytoprotective and antiinflammatory actions of dietary BB can provide metabolic benefits to combat obesity-associated pathology.” Blueberries can combat obesity and its problems.

·        Blueberries make their mark on cardiovascular and diabetes risks, U-M animal study finds, April 2009. “The researchers studied the effect of blueberries (freeze dried blueberries crushed into a powder) that were mixed into the rat diet, as part of either a low- or high-fat diet. They performed many comparisons between the rats consuming the test diets and the control rats receiving no blueberry powder. All the rats were from a research breed that is prone to being severely overweight. — In all, after 90 days, the rats that received the blueberry-enriched powder, measured as 2 percent of their diet, had less abdominal fat, lower triglycerides, lower cholesterol, and improved fasting glucose and insulin sensitivity, which are measures of how well the body processes glucose for energy. — While regular blueberry intake reduced these risks for cardiovascular disease and metabolic syndrome, the health benefits were even better when combined with a low-fat diet.” Blueberries can reduce risk of cardiovascular disease.

·        A blueberry-enriched diet protects rat hearts from ischemic damage,  June 2009. “CONCLUSION: A blueberry-enriched diet protected the myocardium from induced ischemic damage and demonstrated the potential to attenuate the development of post MI chronic heart failure.” Blueberries can help protect against heart attack damage.

·         Antiobesity and antidiabetic effects of biotransformed blueberry juice in KKAy mice, August 2009.  This study is based on Juice extracted from North American lowbush blueberries which has been biotransformed with Serratia vaccinii, a bacteria from the skin of the fruit.  The KKAy mice provide a rodent model of leptin resistance.  “Incorporating BJ (the biotransformed blueberry juice)in drinking water protected young KKAy mice from hyperphagia and significantly reduced their weight gain. Moreover, BJ protected young KKAy mice against the development of glucose intolerance and diabetes mellitus.” “Results of this study clearly show that biotransformed blueberry juice has strong anti-obesity and anti-diabetic potential,” says senior author Pierre S. Haddad, a pharmacology professor at the Université de Montréal’s Faculty of Medicine. “Biotransformed blueberry juice may represent a novel therapeutic agent, since it decreases hyperglycemia in diabetic mice and can protect young pre-diabetic mice from developing obesity and diabetes(ref).”  Biotransformed blueberry juice can be protective against obesity and diabetes.

·        Wild Blueberries May Help Protect Arteries, Reduce Risks From Cardiovascular Disease, November 2003. “The apparent benefit of the blueberry enriched diet carried over to older rats which received blueberries later in the study. The implication is that the addition of wild blueberries to the diet later in life may still have a protective effect on arteries.” Wild blueberries can protect against cardiovascular disease in the old as well as young.

·        Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus, “These results indicate that blueberry polyphenols attenuate learning impairments following neurotoxic insult and exert anti-inflammatory actions, perhaps via alteration of gene expression.” It was observed that blueberries attenuated the expression of NF-kappaB induced by the neurotoxic kainic acid and augmented the expression of IGF-1. Blueberries can be protective of mental capability when exposed to brain toxins.

·        Inhibition of cancer cell proliferation and suppression of TNF-induced activation of NFkappaB by edible berry juice, March-April 2007.  “The potential chemopreventive activity of a variety of small berries cultivated or collected in the province of Québec, Canada were evaluated here. — RESULTS: The growth of various cancer cell lines, including those of stomach, prostate, intestine and breast, was strongly inhibited by raspberry, black currant, white currant, gooseberry, velvet leaf blueberry, low-bush blueberry, sea buckthorn and cranberry juice, but not (or only slightly) by strawberry, high-bush blueberry, serviceberry, red currant, or blackberry juice. No correlation was found between the anti-proliferative activity of berry juices and their antioxidant capacity (p > 0.05). — juice of 6 significantly inhibited the TNF-induced activation of COX-2 expression and activation of the nuclear transcription factor NFkappaB.” Blueberry and other berry juices can be protective against some cancers. 

·        Blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry extracts inhibit growth and stimulate apoptosis of human cancer cells in vitro, December 2006.  “The berry extracts were evaluated for their ability to inhibit the growth of human oral (KB, CAL-27), breast (MCF-7), colon (HT-29, HCT116), and prostate (LNCaP) tumor cell lines at concentrations ranging from 25 to 200 micro g/mL. With increasing concentration of berry extract, increasing inhibition of cell proliferation in all of the cell lines were observed, with different degrees of potency between cell lines.”  Blueberry and other edible berry extracts can kill cancer cells.

·        Berry fruits: compositional elements, biochemical activities, and the impact of their intake on human health, performance, and disease, February 2008.  “An overwhelming body of research has now firmly established that the dietary intake of berry fruits has a positive and profound impact on human health, performance, and disease.” Blueberries and other berries are great for health.

·        Whole berries versus berry anthocyanins: interactions with dietary fat levels in the C57BL/6J mouse model of obesity, February 2008.  “After 8 weeks, mice fed the HF60 (high fat) diet plus purified anthocyanins from BB in the drinking water had lower body weight gains and body fat than the HF60-fed controls. Anthocyanins fed as the whole blueberry did not prevent and may have actually increased obesity. However, feeding purified anthocyanins from blueberries or strawberries reduced obesity.”  The berries used in the study were blueberries and strawberries.This study is interesting because it suggests the additional calories from the whole berries possibly led to weight gain but the anthocyanin extracts led to weight loss.  If this result is further confirmed, it would provide an argument for consuming berry anthocyanin extracts supplements instead of the whole berries themselves. Berry anthocyanin supplements might be better for weight loss than the berries themselves.

·        Purple Berries’ Rank High In Antioxidants, USDA Study Says, November 2003.  Some berries may be even better for you than blueberries, ones like elderberries, black currants and chokeberries.  “In preliminary laboratory studies, the researchers found that the elderberry, black currant and chokeberry — collectively known as the “purple berries” due to their dark color — are as much as 50 percent higher in antioxidants than some of the more common berry varieties and have the potential to provide more health benefits, such as protection against cancer, heart disease and Alzheimer’s.”  The darker and more purple the berry colors the better thay are for you, possibly.

Defined-benefit pension plans (DBPPs) are ones that pay out a fixed monthly amount for the life of the pensioner, possibly with a cost-of-living adjustment for inflation.  Social Security in the US is a prime example.  There are thousands of other defined-benefit pension plans worldwide sponsored by governments and government agencies, corporations, insurance companies, not-for-profits, unions, financial trusts, etc.  What DBPPs share in common is being financially ambushed by rapidly increasing longevity in the general population.

These plans traditionally have been designed so that income and outgo of a pension fund would balance for the population concerned taking multiple variables into account, among these being actuarial statistics for longevity of a plan’s participants.  Traditionally these life-expectancy statistics have been slow-changing.  So, in setting up a new plan changes in life expectancy could be ignored or accommodated by a built-in general contingency margin.  That is the way it was in the 1930s and 1940s. So what happens when the plans are faced with “runaway longevity,” life expectancy growing to be far beyond that expected?   The answer is financial crises and unsustainability for the DBPPs concerned. 

Even without extraordinary longevity as advocated in this blog, many existing DBPPs are already having serious financial problems with their participants living longer than expected.  According to an article appearing yesterday in the UK Times Online, “Directors and pension trustees have already been cruelly mauled by the British population’s habit of living longer than expected, drawing extra pension payments in the process. In the past 12 months UK longevity forecasts have risen by a year, sufficient to increase the combined FTSE 100 pension deficit by £1m an hour, according to Hewitt Associates, a firm of actuaries(ref).”  If that rate of longevity increase is correct and keeps up – growing by a year in 12 months, it sounds like pension funds that expected participants to behave right and die off in 15 years might have to keep paying them off forever.

One response of DBPPs has been to close down to new participants; another has been to cap cost-of-living increases; many have gone into deep deficit. “Some groups with large deficits in their defined-benefit schemes have gone farther, stopping existing members from accruing new benefits. Others have chosen a middle course. Royal Bank of Scotland last week said it would cap increases in benefits at the rate of inflation or 2%, whichever was the lower. The news did not go down well with the 60,000 affected employees, who had watched Sir Fred Goodwin, the chief executive, leave with a £17m retirement package.” – “Longevity, however, has silently crept up on trustees and companies, and has provided a nasty surprise.  — Pension schemes are, at the moment, having to deal with a “bulge” in longevity caused by the health improvements made in the past 20 years. Once this spurt has been dealt with, trustees think they should be all right if they assume perhaps an increase of 1% or 2% each year. They might not. “The problem with estimating longevity is that many of the judgments are subjective. You don’t know how long people will live,” said Martin Bird, the UK lead on longevity at Hewitt(ref).”

I also think it might be a mistake to view the current rate of longevity increase as a “bulge” or “spurt.”  I suspect the rate may actually grow higher instead of going down. See the May 2009 blog entry The Social ethics of longevity. There I argued that social evolution requires that people live longer – and is in fact leading to longer and longer life spans. Also see the blog entry Average US life expectancy is up 73 days in one year.  (I am not sure, by the way, the Times article was correct in stating that life expectancy in Great Britain increased a year over a year-long period even though the main point of the article is correct.)

DBPPs have been on their way out for several years now, being replaced by defined-contribution plans.  These are plans like IRAs where the retiree benefits are not fixed but are based on what the retiree wishes to draw out from a pot of money put into the plan during working years and invested.  In the US at least, money in such a plan can be grown tax-free.   Nonetheless, DBPPs have a long history and strong supportive constituencies.  A history of Social Security in the US going back to 1600 can be found here.  Keeping the existing DBPPs going in the face of increasing longevity is likely to become a very contentious process, pitting “entitled” pensioners against “realist” financial managers.  I expect the future political process associated with social security reform in the US will make the current health-system reform fight seem like a very tame game. 

A major impediment to developing drugs that affect the brain, such as new treatments for Alzheimer’s Disease, Meningitis , Epilepsy, Parkinson’s disease and Multiple sclerosis, has been determining whether and how effectively a drug substance can cross the blood-brain barrier (BBB).  The barrier separates cerebrospinal fluid surrounding the brain from circulating blood and is highly selective in the molecules it lets through.  Physically, the barrier is created by “tight junctions between endothelial cells in CNS vessels that restricts the passage of solutes.”   The cells line some 400 miles of tiny capillary vessels throughout the brain. The barrier is neuroprotective and keeps out many common bacteria, but “In its neuroprotective role, the blood-brain barrier functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain. Therapeutic molecules and genes that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts(ref).”

The blood-brain barrier stands in the way of new drug development(ref).  Specifically, most large-molecule drugs cannot pass through it, so testing the safety and efficacy of many possible new therapeutic agents for the brain poses a serious challenge.

Triple quadrupole mass spectrometry offers a way of working around this problem.  A triple quadrupole mass spectrometer is a sophisticated laboratory device about the size of a table-top refrigerator.  Technically, “A triple quadrupole mass spectrometer is a tandem mass spectrometer (TQMS) consisting of two quadrupole mass spectrometers in series, with a (non mass-resolving) radio frequency (RF) only quadrupole between them to act as a collision cell for collision-induced dissociation. The first (Q₁) and third (Q₃) quadrupoles serve as mass filters, whereas the middle (q₂) quadrupole serves as a collision cell(ref).”  

A TQMS can help determine exactly how much of a substance is getting through to the brain and is being used, for example, in research on drug treatments for Alzheimer’s disease.  As reported in the Aug 1 issue of GEN, “Another state-of-the-art tool, triple quadrupole mass spectrometry, gives scientists at Mithridion an advantage for working in the Alzheimer’s drug arena. Triple quadrupole mass spectrometry measures accurately and quantitatively small amounts of drugs in an extract of blood or brain tissue during preclinical studies. In Alzheimer’s disease research, it’s critical to confirm that new drug candidates are capable of crossing the blood-brain barrier to work in the brain. “The blood-brain barrier is quite an obstacle, and many drugs fail to get through,” Dr. Twose notes. — Not only does triple quadrupole mass spectrometry confirm that compounds enter the brain, but the technology also defines chemical structures required for this to happen. “We know many of the rules, so we can carry out an in silico process before we synthesize compounds,” continues Dr. Twose. Mithridion’s semi-rational approach to drug design provides a good estimate of whether compounds will pass into the brain, and triple quadrupole mass spectrometry verifies that this occurs(ref).”

The triple quadrupole mass spectrometer is an example of hundreds of new technologies that are helping accelerate the pace of medical and life sciences research and facilitating discoveries that will at some point allow us to live for centuries.  In proposing Giuliano’s Law which relates to the prospects for breaking through the 122 year human age limit, I asserted that improving technology was combining with several other factors to constantly accelerate the rate of discovery and availability of anti-aging interventions.  For a complete discussion of how these factors are combining to drive the acceleration, see the blog post Factors that drive Giuliano’s Law.  Finally if you want to get a sense of some of the other emerging technologies that are being put to work for life sciences discovery, development, and production, I suggest you browse through a copy of GEN (Genetic Engineering & Biotechnology News), a biotechnology industry trade newspaper-magazine.  Our daily newspapers are getting skinnier, but GEN seems constantly to be getting fatter.

New cohort studies were published in the last few weeks on the impact of following the Mediterranean diet on the risk of senile dementia.  This led me to do a quick review of the research behind the general wisdom that the diet “is good for you.”  I summarize what I found here.

I suggest following the Mediterranean diet in numerous places in my treatise ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY.   I wrote “Consider a Mediterranean Diet which features eating lots of vegetables and fruits, lean protein, fish, whole-grain pasta, lots of olive oil and moderate amounts of red wine.”  Actually the Mediterranean Diet (MeDi) is a family of somewhat similar diets commonly followed in different countries bordering the Mediterranean.  Key components of the diet from a health viewpoint are described here and include:

§  “Getting plenty of exercise and eating your meals with family and friends

§  Eating a generous amount of fruits and vegetables

§  Consuming healthy fats such as olive oil and canola oil

§  Using herbs and spices instead of salt to flavor foods

§  Eating small portions of nuts

§  Drinking red wine, in moderation, for some

§  Consuming very little red meat

§  Eating fish or shellfish at least twice a week(ref)” 

First, as to the new research relating the diet to risk of dementia:  An August 12 study 2009 report in JAMA Adherence to a Mediterranean diet, cognitive decline, and risk of dementia is a “ cohort study of 1410 adults (> or = 65 years) from Bordeaux, France, included in the Three-City cohort in 2001-2002 and reexamined at least once over 5 years.” – “CONCLUSIONS: Higher adherence to a Mediterranean diet was associated with slower MMSE (Mini-Mental State Examination) cognitive decline but not consistently with other cognitive tests(ref).”  The conclusions were reached based on data adjusted  “for age, sex, education, marital status, energy intake, physical activity, depressive symptomatology, taking 5 medications/d or more, apolipoprotein E genotype, cardiovascular risk factors, and stroke.” 

A second report in the same issue of JAMA Physical activity, diet, and risk of Alzheimer disease looks at the impact of following the Mediterranean diet in combination with substantial physical activity.  This is a “Prospective cohort study of 2 cohorts comprising 1880 community-dwelling elders without dementia living in New York, New York.  Standardized neurological and neuropsychological measures were administered approximately every 1.5 years from 1992 through 2006.”  Again, the data was adjusted for numerous variables. “Compared with individuals neither adhering to the diet nor participating in physical activity (low diet score and no physical activity; absolute AD (Alzheimer Disease) risk of 19%), those both adhering to the diet and participating in physical activity (high diet score and high physical activity) had a lower risk of AD (absolute risk, 12%; Hazard Ratio, 0.65 [95% CI, 0.44-0.96]; P = .03 for trend). – Conclusion”  In this study, both higher Mediterranean-type diet adherence and higher physical activity were independently associated with reduced risk for AD(ref).”

A July 2009 study report looks at Mediterranean diet and mild cognitive impairment.  The study is based on data from a multi-ethnic community in New York. “There were 1393 cognitively normal participants, 275 of whom developed MCI (mild cognitive impairment) during a mean (SD) follow-up of 4.5 (2.7) years (range, 0.9-16.4 years).”  Subjects were divided into tertiles with respect to their adherence to a Mediterranean diet. “CONCLUSIONS: Higher adherence to the MeDi is associated with a trend for reduced risk of developing MCI and with reduced risk of MCI conversion to AD(ref).”

I mention two other studies relating the MeDi to dementia risk.  A 2007 study report of 192 individuals looked at Mediterranean diet and Alzheimer disease mortality . “ CONCLUSION: Adherence to the Mediterranean diet (MeDi) may affect not only risk for Alzheimer disease (AD) but also subsequent disease course: Higher adherence to the MeDi is associated with lower mortality in AD. The gradual reduction in mortality risk for higher MeDi adherence tertiles suggests a possible dose-response effect(ref).”  Another 2007 study was on Mediterranean diet, Alzheimer disease, and vascular mediation.  “CONCLUSIONS: We note once more that higher adherence to the MeDi is associated with a reduced risk for AD. The association does not seem to be mediated by vascular comorbidity(ref).”

All five of these cohort studies show a consistent correlation between following a MeDi and lower risk of age-related dementia. The studies correlating Mediterranean Diet to lower mortality are even more impressive. Of many relevant publications I cite only two important studies.  The first is a 2007 report Mediterranean dietary pattern and prediction of all-cause mortality in a US population: results from the NIH-AARP Diet and Health Study.  “Study participants included 214,284 men and 166,012 women. — During follow-up for all-cause mortality (1995-2005), 27,799 deaths were documented. In the first 5 years of follow-up, 5,985 cancer deaths and 3,451 cardiovascular disease (CVD) deaths were reported.” – “The Mediterranean diet was associated with reduced all-cause and cause-specific mortality.” – “. In women, an inverse association was seen with high conformity with this pattern: decreased risks that ranged from 12% for cancer mortality to 20% for all-cause mortality (P = .04 and P < .001, respectively, for the trend). — CONCLUSION: These results provide strong evidence for a beneficial effect of higher conformity with the Mediterranean dietary pattern on risk of death from all causes, including deaths due to CVD and cancer, in a US population(ref).”

The second cohort study looking at MeDi and mortality is Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. The study “includes 1507 apparently healthy men and 832 women, aged 70 to 90 years in 11 European countries. This cohort study was conducted between 1988 and 2000.” – “CONCLUSION: Among individuals aged 70 to 90 years, adherence to a Mediterranean diet and healthful lifestyle is associated with a more than 50% lower rate of all-causes and cause-specific mortality(ref).”

These and similar reductions in mortality and other benefits of a Mediterranean diet reported in other publications are quite impressive to me.  The reasons for following a Mediterranean diet and a healthy lifestyle are not just New-Age fluff.

This is about alpha melanocyte-stimulating hormone tripeptide K(D)PT.   In the blog post Anti-inflammatory effects of the hormone alpha-MSH, I discussed a line of research linking the human hormone alpha-melanocyte-stimulating hormone (alpha-MSH) to reduction of inflammation.  Alpha-MSH is synthesized in human hair follicles and acts upon melanocytes, cells which produce the pigment melanin which gives color to the skin, eyes and hair.  In that post I discussed how alpha-MSH effectively controls systemic inflammation through acting on the central nervous system and inhibiting the expression of NF-kappaB.   “The anti-inflammatory effects of alpha-MSH have been confirmed by means of animal models of inflammation such as irritant and allergic contact dermatitis, cutaneous vasculitis, asthma, inflammatory bowel disease, rheumatoid arthritis, ocular and brain inflammation(ref).”

Another substance closely related to alpha-MSH is attracting increasing interest as a possible anti-inflammatory agent, that being K(D)PT   “Most of the anti-inflammatory activities of alpha-MSH can be attributed to its C-terminal tripeptide KPV. K(D)PT, a derivative of KPV corresponding to the amino acid 193–195 of IL-1beta, is currently emerging as another tripeptide with potent anti-inflammatory effects. The anti-inflammatory potential together with the favourable physiochemical properties most likely will allow these agents to be developed for the treatment of inflammatory skin, eye and bowel diseases, allergic asthma and arthritis(ref).”  K(D)PT is identical to interleukin (IL)-1beta193-195.  Like alpha-MSH, K(D)PT appears to be an anti-inflammatory that inhibits the expression of NF-kappaB. K(D)PT “ameliorates endotoxin-induced nuclear factor kappaB translocation(ref)” 

Regular readers of this blog know I have an interest in the role of hair follicle melanocytes in hair pigmentation, a subject I discussed in the blog posts Why does your hair turn gray, and More research insight on gray hair and adult stem cell reproduction.  K(D)PT appears to be capable of stimulating hair pigmentation under inflammatory conditions that would normally turn colored hair gray.  “The alpha-melanocyte stimulating hormone-related tripeptide K(D)PT stimulates human hair follicle pigmentation in situ under proinflammatory conditions.”  “Conclusions: The IL-1beta- and alpha-MSH-related tripeptide, K(D)PT, displays interesting hair pigmentation-stimulatory activities under proinflammatory conditions. These might become exploitable for innovative antigreying strategies, notably in postinflammatory poliosis (regrowth of white hair, e.g. during recovery from alopecia areata), where no effective clinical therapy is yet available(ref).”

The research relating K(D)PT to human hair pigmentation is still in an early stage.  It is possible that this substance could turn out to be a useful new anti-inflammatory and could also play a role in restoring natural color to gray hair under certain stress circumstancces.

A new study just published  in the New England Journal of Medicine points out yet-again the growing risk due to low-level radiation associated with the increasing use of CAT scans and other sophisticated radiological procedures.  The study looked at the cumulative radiation received by “952,420 nonelderly adults (between 18 and 64 years of age) in five health care markets across the United States between January 1, 2005, and December 31, 2007.”  — “Computed tomographic and nuclear imaging accounted for 75.4% of the cumulative effective dose, with 81.8% of the total administered in outpatient settings.” – “Conclusions: Imaging procedures are an important source of exposure to ionizing radiation in the United States and can result in high cumulative effective doses of radiation(ref).”

As most readers here probably know, oxidative damage is the oldest and most established theory of aging and ionizing radiation is a prime source of free radicals (reactive oxidative species, or ROS).  In short, the medical radiation can be a prime source of aging.  The increase in use of CAT scans is part of a shift in the general practice of medicine.  The orders for the CAT scans come not from the radiologists who read the results but from other doctors who see them as part of their regular diagnostic toolkit, like cardiologists, oncologists, pulmonologists, rheumatologists and especially emergency room doctors.  Some patients with chronic diseases may undergo a half-dozen or more CAT scans a year.

While avoiding the CAT scans and the associated radiation may be difficult or unwise given the change in the practice of medicine, there is another approach that can contribute to minimizing the radiation damage.  I wrote a paper treating this subject in 2008 which is available online Protection Against Radiation – The Second Line of Defense.  Basically, the protective idea is to take antioxidants.  I suggest reading this paper for anyone expecting to undergo extensive diagnostic x-radiation.  I repeat the summary of this paper here.

SUMMARY 

The increasing use of diagnostic radiology is unquestionably beneficial.  However, per-capita exposure to medical radiation has grown some six fold in the last two decades and appears to be still increasing.  The issue of medical radiation protection is therefore achieving central importance for the health of both patients and radiation professionals.   It is well established that the effects of radiation are cumulative and lead to increased incidence of cancers, cell deaths, genetic damage and numerous forms of body tissue pathology.   

The first line of defense against gamma and X radiation damage, long established in clinical practice, is simply radiation avoidance such as by use of shorter exposure and more sensitive film, carefully focused beams, lead aprons and other shielding. 

This paper is concerned with a second and complimentary line of defense one not yet established in clinical practice but potentially of great importance.  That is, radiation damage minimization by interfering with the biological mechanism of radiation damage, that is, interfering with the propagation in tissues of free radicals created by X-rays.  This kind of protection can be achieved through using commonly-available antioxidant supplements.   

Despite the large body of research supporting the effectiveness of antioxidants to quench radiation-induced free radicals, this second line of defense against radiation damage is neither taught to radiology students in medical schools nor is embodied in general clinical radiology practice. The author discusses the research basis for widespread adoption of this “second line of defense” for radiation protection and provides some 60 research citations to support his points. 

The paper also discusses the use of specific antioxidants for radiation protection and cites some 60 studies on the radioprotectivity of specific antioxidants.  The paper is relevant not only to patients but also to interventional radiologist, radiation technicians and atomic-technology workers who are repeatedly exposed to low doses of ionizing radiation.